ReviewArticle Pathways to Breast Cancer Recurrence...ISRNOncology 3 Early intervention and treatment...

Hindawi Publishing CorporationISRN OncologyVolume 2013 Article ID 290568 16 pageshttpdxdoiorg1011552013290568

Review ArticlePathways to Breast Cancer Recurrence

Aamir Ahmad

Department of Pathology Karmanos Cancer Institute Wayne State University School of Medicine Detroit MI 48201 USA

Correspondence should be addressed to Aamir Ahmad ahmadakarmanosorg

Received 13 December 2012 Accepted 17 January 2013

Academic Editors C Perez Y Wu and W Yang

Copyright copy 2013 Aamir AhmadThis is an open access article distributed under theCreativeCommonsAttribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Breast cancer remains a deadly disease evenwith all the recent technological advancements Early intervention hasmade an impactbut an overwhelmingly large number of breast cancer patients still live under the fear of ldquorecurrentrdquo disease Breast cancer recurrenceis clinically a huge problem and one that is largely notwell understoodOver the years a number of factors have been studiedwith anoverarching aim of being able to prognose recurrent disease This paper attempts to provide an overview of our current knowledgeof breast cancer recurrence and its associated challenges Through a survey of the literature on cancer stem cells (CSCs) epithelial-mesenchymal transition (EMT) various signaling pathways such as NotchWnthedgehog and microRNAs (miRNAs) we alsoexamine the hypotheses that are currently under investigation for the prevention of breast cancer recurrence

1 Breast Cancer The Problem

Breast cancer is a major health problem that affects the livesof millions For the year 2012 it was estimated that 226870women in theUnited Stateswill be diagnosedwith breast can-cer and that 39510womenwill succumb to it [1 2]With thesenumbers breast cancer is the leading cancer diagnosed in theUS women and is second only to lung cancer in terms of totalfatalities [1] It is generally recognized that much scientificadvancements have been made in the area of breast cancerresearch and it is because of these efforts that the chances ofdisease-free survival of breast cancer survivors have increasedtremendously over the last few decades However this appliesonly if the breast cancer is diagnosed at an early stage and islimited to the primary organOnce breast cancermetastasizesto other organs the therapeutic options are very limitedand the success rate of managing such patients in clinics isdismal

The challenges in managing breast cancer patients arevery many First of all although many risk factors have beenassociated with the possible initiation and progression ofdisease nothing concrete is established that can potentiallyprevent the primary disease or its progression andmetastasesAdditionally there are well-studied disparities in breastcancer that include socioeconomic disparities [3] as well as

the racial disparities [4] All this information seems to suggestthat no two women have equal chances of developing thedisease Even when comparing among breast cancer patientsthere are not very reliable predictors of aggressiveness

The advanced stage breast cancers are broadly char-acterized by one or both of thesemdashmetastases and drugresistance Metastases to organs such as lungs bones brainand liver severely limit the option of surgical interventionand also suffer from the lack of targeted therapies Drugresistance is another challenge that is clinically very relevantMany breast cancer patients do not respond to targetedtherapies from the start and this is called de novo drugresistance A number of breast cancer patients howeverdo respond to targeted therapies such as tamoxifen andtrastuzumab and show signs of improvement initially onlyto turn refractory to these treatments with the passage oftime called acquired resistance [5 6] Metastases as wellas drug resistance phenotypes almost always result in poorprognosis and a disease condition that is progressivelyaggressive

As mentioned previously a breast cancer patient has verygood chances of a disease-free survival if the cancer is caughtand treated early It is important to mention that the termldquoearlyrdquo is very subjective Inmany cases the cancer is thoughtto have been treated early only to discover its reappearance

2 ISRN Oncology

years after the first intervention (Figure 1)This phenomenonis ldquotumor recurrencerdquo and the subject of our discussion here

2 Breast Cancer Recurrence

Recurrence of breast cancer is a major clinical manifestationand represents the principal cause of breast cancer-relateddeaths [7] A number of researchers have tried to predictsome sort of pattern for breast cancer recurrence This hasincluded studies in various breast cancer subtypes whereinbreast cancers are characterized by the presence of receptorssuch as estrogen receptor (ER) progesterone receptor (PR)and HER2ErbB2 receptor (HER2) or by the absence ofall of them the triple negative breast cancers (TNBCs) Adifferential pattern of recurrence between different breastcancer subtypes has been suggested and it appears [8ndash10]that ER-negative breast cancers are associated with higherrisk of recurrence during the initial 5 years after diagnosiscompared to ER-positive breast cancers Thereafter the riskof recurrence chronically increases in ER-positive breastcancers for the next 10 years and at 15 years followingdiagnosis the risk appears to be equal for both subtypesIn ductal carcinoma in situ it has been analyzed that theER-negativePR-negative but HER2-positive cancers havehigher risk of recurrence compared to ER-positivePR-positiveHER2-negative cancers [11] The TNBCs markedby absence of ERPRHER2 are generally associated withhigh risk of recurrence with particularly high risk of distantrecurrences in brain and visceral metastases compared toreceptor positive tumors [12]

In addition to the simple classification of breast cancersdescribed previously there are other subclassifications ofbreast cancers as well such as the one that classifies breastcancers into luminal A luminal B basal and HER2 enriched[13] The luminal A subtype includes ER-positive andorPR-positive HER2-negative breast cancers luminal B sub-type includes ER-positive andor PR-positive HER2-positivebreast cancers basal subtype includes ER-negative PR-negative HER2-negative breast cancers which may also bepositive for EGFR and HER2-enriched subtype includes ER-negative PR-negative and HER2-overexpressing breast can-cers The existence of such subtypes which are at time over-lapping but most of the time so distinct presents a challengeto the choice of appropriate therapy This has led to the pro-posal of personalized therapy that fits the needs of individualpatients

Irrespective of the underlying breast cancer subtype alarge number of advanced stage breast cancers are markedby metastases to lymph nodes and overall the presenceof axillary lymph node metastases is associated with con-siderable poor disease-free as well as overall survival [14]Axillary lymph node metastases remain a very importantprognostic variable and identification of molecular markersfor development of lymph node metastases can potentiallyhelp intervene early reducing the chances of breast cancerrecurrence [15]

3 Cancer Recurrence in Breast CancerPatients Undergoing Surgery

Surgical intervention is one of the options for breast cancerpatients [16] The choice for surgical intervention largelydepends on the cancer stage For patients presenting withearly stage breast cancer the two most common treatmentoptions available are breast conserving surgery followed byradiation therapy ormastectomy [17ndash19]Mastectomyusuallydoes not need subsequent radiation therapy It seems thatthere are distinct risk factors of recurrence in breast can-cer patients undergoing mastectomy versus those choosingbreast conserving therapy [20]Whereas lymphnode involve-ment and tumor size are major risk factors after mastectomythe young age and presence of ductal carcinoma in situare major risk factors after breast conservation therapy Thedistinct clinical and histopathological determinants resultin differential response to radiotherapy and point to theneed for more robust personalized therapies and follow-up procedures for patients opting for different surgicalinterventions Further complicating the decision of surgeonsperforming breast conserving therapy is the realization thatsurgical margins also seem to impact the recurrence of breastcancer [21] In a study [17] that scanned published reportsand systematically reviewed the local recurrence in breastcancer patients undergoing mastectomy with or withoutbreast reconstruction it was concluded that the recurrencerates were not higher in patients that underwent breastreconstruction Also radiation therapy is generally associatedwith reduced recurrence in breast cancer and a recent meta-analysis [22] of 10801 patients from 17 randomized trials hasconcluded that radiotherapy reduces the recurrence rate byhalf and the death rate by about a sixth in patients that haveundergone breast conserving surgery Interestingly this studyalso identified many factors that might influence the extentof radiotherapy-induced benefits Such factors include agecancer grade estrogen receptor status and use of tamoxifenas well as the extent of surgery

In a study [23] that looked at the influence of molecularsubtypes of breast cancers namely ER-positive PR-positiveand HER2-overexpressing as well as TNBC in relation torecurrence in patients with mastectomy versus breast con-serving surgery a differential rate of recurrence was observedin patients with different molecular subtypes This studyanalyzed data from 15 different studies covering a total of12592 patients of which 57 underwent breast conservingtherapy while 43 underwent mastectomy It was observedthat among the patients that underwent breast conservingtherapy patients with ER-positive and PR-positive breastcancers had many reduced instances of recurrence thanHER2-overexpressing and TNBC patients Similar resultswere observed for mastectomy patients as well where ER-positive and PR-positive patients were again found to be at alesser risk of recurrence compared to HER2-overexpressingand TNBC patients Although both HER2-overexpressingand TNBC patients were found to be at a higher risk of recur-rence a direct comparison between the two subtypes revealedthat HER2-overexpressing breast cancer patients presentedhigher risk of recurrence in patients undergoing breast

ISRN Oncology 3

Early interventionand treatment

Primary localized tumor

Apparent tumorregression

Metastatictherapy-resistant

tumor

Cancer cellCancer stem cellCancer cell with aggressivephenotype through modulationof signaling pathways andor miRNAs

Time lapse

Figure 1 Current understanding of breast tumor recurrence Breast cancers localized at primary breast location and treated early can stillrelapse due to (a) existence of cancer stem cells and (b) transformation of cancer cells into a relatively aggressive phenotype Cancer stemcells as well as transformed cancer cells are resistant to conventional therapies and highly metastatic Recurrent breast cancers are typicallymarked by high percentage of aggressive cells

conserving surgery In the mastectomy patients the risks ofrecurrence in HER2-overexpresing and TNBC patients wasnot found to be statistically different This analysis identifieda differential risk of breast cancer recurrence in patientswith different molecular subtypes and underlines the need toconsider breast cancer subtype while managing breast cancerpatients for disease-free survival

In the context of ipsilateral breast tumor recurrencesafter breast conserving surgery two interesting hypotheseshave been proposed [24] which seek to better define ourunderstanding of true tumor recurrences First of all ithas been proposed that the local recurrences might actuallyinitiate long before the diagnosis of primary tumor andmay be recorded as multifocal primary tumor at the timeof diagnosis and secondly true local recurrences mightactually never metastasize to distant organs Breast cancerwas proposed as an ideal cancer for such studies because ofthe availability of enormous clinical data for analysis Anotherinteresting theory for cancer recurrence is the wound-oncogene-wound healing (WOWH) hypothesis [25] which isbased on the observed interrelationships between precancer-ous lesions cancer oncogenes wound healing and cancerrecurrence The essence of this theory is that the ldquowoundsrdquoexemplified by physical (such as radiations) chemical (suchas carcinogens) and biological (such as inflammation agingand reactive oxygen species) damages trigger the oncogenesto produce cytokines resulting in recruitment of stem cellsand tissue remodeling All this leads to generation of cancermass particularly with continued existence of wounds andultimately results in death of the organism

4 Molecular Factors That InfluenceBreast Cancer Recurrence

It is evident that breast cancer is particularly lethal when itrecurs The causes for such breast cancer recurrence remaincompletely unknown except for many putative molecularmarkers that are under active investigation for their possiblerole in determining the recurrence This section discussesmany such factors with emphasis on studies that have linked

individual moleculessignaling factors with breast cancerrecurrence andor disease-free survival

41 Cancer Stem Cells Over the last few decades a number ofhypotheses have been proposed to explain tumor recurrencesuch as clonal selection angiogenic dormancy and morerecently CSCs [26 27] CSCs are cells within populationsof cancer cells or tumors which possess the capacity toself-renew and produce heterogeneous lineages of cancercells [28] CSCs by virtue of being stem cells have tumor-initiating capabilities CSCs are now believed to persist intumors as distinct populations that are fundamentally associ-ated with drug resistance tumor recurrence and metastasisOur inability to prevent tumor recurrence in clinics pointsto the fact that the knowledge of underlying factors is not yetmature enough andmuchmore needs to be doneWhile CSCtheory appears to be attractive it has its own pitfalls [29] Anumber of molecular pathways have been proposed to playa role in maintenance of CSC phenotype which is furthercomplicated by the observation that none of the molecularmarkers of CSCs seems to be universally relevant Most of theresearch is cancer specific and the factorspathways relevantin one cancer may or may not be relevant targets for therapyin other cancers

The majority of research investigations on the role ofCSCs in tumor recurrence have focused on their role inthe context of resistance against chemotherapy however itis increasingly being advocated that CSCs determine theresistance to radiation therapy as well When tumors aresubjected to radiation therapy as part of the anticancertherapy CSCs still thrive and a higher proportion of CSCscorrelates with increased resistance to radiation therapy [30]Multiple signaling pathways in breast CSCs determine theirresistance to radiations such as heat shock protein 27 (hsp27)EMT and NF-120581B signaling [31] A number of mechanismsare believed to contribute to the CSCs-induced resistanceto drugs and tumor recurrence and these include quies-cence upregulation of ABC transporters highly efficientDNA repair systems and upregulation of several signalingpathways [32] (Figure 2) Quiescence is the state of temporary

4 ISRN Oncology

Cancer stem cell

Induced NotchWntHh signaling

UpregulatedABC transporters

Induction of EMT

Modulated miRNAs

Quiescence

IncreasedDNA repair

Figure 2 Multiple factors that define the ldquostemnessrdquo in cancer stemcells

inactivity The role of quiescence in CSCs activity has itsbasis in the observation that a number of chemotherapeuticregimes target rapidly proliferating cancer cells Thus CSCsthrough their ability to proliferate slowly with intermittentphases of quiescence are able to evade the cytotoxic effects ofanticancer drugs The role of ABC transporters in drug resis-tance of cancer cells has long been advocated [33 34] Drug-resistance mechanisms can either interfere with the deliveryof drugs to tumor cells or arise within the cancer cells suchas ABC transporters leading to alterations in drug sensitivityABC transporters increase the drug efflux from tumor cellsleading to reduced intracellular drug concentrations whichare not cytotoxic enough Drug resistance mediated by ABCtransporters is believed to mediate resistance against theentire class of drugs as opposed to being drug specificThis is why resistance against anticancer drugs paclitaxeldoxorubicin or vinblastine is frequently due to increasedexpression of ABC transporters [33 35] ABC transportersare upregulated in hematopoietic stem cells supporting theirrole in conferring stem cell-like phenotype [34 36ndash38] andthe drug resistance of CSCs [39 40]

During the last several years a role of CSCs in tumorprogression metastasis and angiogenesis has been estab-lished [41ndash44] Breast cancer is in the forefront of ongoingstudies on the role of CSCs in mediating metastasis as wellas resistance to current pharmaceutical regimes and this isbelieved to involve a complex interplay of several cell typescytokines cell growths and signaling pathways [45 46] Alsoa number of cell surface markers such CD44 (high)CD24(low)ALDH-positive have been associated with the CSCs[47] A number of putative molecular markers of CSCs arebeing pursued for in-depth clinical studies [48 49] Thephenomena of drug resistance and tumor recurrence areintricately related because in order to recur cancer cells needto overcome the cytotoxic effects of drugs that are used tocontrol the growth of these cancers in clinics Thus drugresistance mediated by CSCs goes hand in hand with thetumor recurrence [50]

42 Epithelial-Mesenchymal Transition The process of EMThas attracted much interest in recent years with regard to

breast cancer aggression Its association with CSC phenotypefurther underscores its importance in recurrence of breasttumors [51ndash53] Progression of most carcinomas towardsmalignancy is associated with the loss of epithelial differen-tiation and a switch toward mesenchymal phenotype whichis accompanied by increased cell motility and invasion Theprocess of EMT by which epithelial cells undergo remarkablemorphological changes is characterized by a transition fromepithelial cobblestone phenotype to elongated fibroblasticphenotype This process involves loss of epithelial cell-celljunction actin cytoskeleton reorganization and upregulationof mesenchymal molecular markers such as vimentin ZEB-1ZEB-2 fibronectin and N-cadherin [54] A disassembly ofcell-cell junction including downregulation and relocationof E-cadherin and zonula occludens-1 as well as downregu-lation and translocation of 120573-catenin from cell membrane tonucleus is known to be the mechanism for the induction ofEMT [55] Epithelial cells have a regular cell-cell junction andadhesion which inhibits cell movement of individual cells Incontrast mesenchymal cells have weaker adhesion betweencells compared to their epithelial counterparts which rendersmesenchymal cells more motile functions and confers moreinvasive characteristics In addition to classical markers ofEMT such as E-cadherin vimentin and ZEB-1ZEB-2 theprocess of EMT is also influenced by several other signalingmolecules particularly those from Notch and Wnt signalingpathways

Since a switch from epithelial tomesenchymal phenotypeis a good indicator of aggressiveness of cancer cells it isdesirable for an anticancer agent to reverse this phenomenonthat is revert back frommesenchymal to epithelial phenotype(MET) [56] An upregulation of epithelial markers andordownregulation of mesenchymal markers is considered areliable indication of the ability of any therapeutic agent toreverse EMT thereby reducing the invasion and metastasisof cancer cells [57] In an early report on the subject snailexpression was shown to induce EMT which also correlatedwith levels in recurrent tumors in vivo [7] Mechanistically itwas shown that snail was sufficient to not only induce EMTin primary tumor cells its induced levels predicted reducedrelapse-free survival and promoted breast tumor recurrencein vivo A review of public databases of breast cancer furthersupported such role of snail1 in breast cancer recurrence [58]Another study on breast cancer cohort also supported a linkbetween snail twist and significantly reduced relapse-freesurvival [59] Since snail and twist regulate E-cadherin andN-cadherin expression the recurrent tumors also expressedreduced E-cadherin and increased N-cadherin It has beensuggested that whereas snail activity is required for EMTinitiation twist plays a role in the maintenance of EMT[60] Such interplay and spatial cooperation of these factorsare crucial to the process of breast cancer metastasis andpredictive of tumor recurrence The role of twist and N-cadherin inEMTof breast cancer cells has beendemonstratedin other investigations as well [61]

The role of TGF-120573 in EMT of breast cancer is well under-stood [62ndash65] In a study suggestive of adverse effects of anti-cancer drugs doxorubicin was demonstrated to induce TGF-120573-driven EMT that could result in CSCs and the resistance to

ISRN Oncology 5

Table 1 Evidence supporting a role of EMTmarkers in breast tumorrecurrence

EMT marker Expression in recurrentbreast tumors Reference

E-Cadherin Low [59 69]N-Cadherin High [59]Slug High [69]Snail High [7 58 59]Twist High [59 61]Vimentin High [69]

chemotherapy [66] This is another indication of a complexrelationship between EMT CSCs drug resistance and thebreast cancer recurrence The TGF-120573-induced EMT and theresulting CSC phenotype have also been characterized as theones with low claudins [67] Such claudin-low phenotypeis marked by increased resistance to oxaliplatin etoposideand paclitaxel A link between cell cycle regulatory cyclin D1and EMT has also been reported [68] A recent study [69]evaluated the correlation if any between EMT markers andpoor clinical outcome The EMT markers chosen were E-cadherin vimentin and slug Immunohistochemical analyseswere done on samples from 441 patients and the patientswere followed up for data on survival A high expressionof mesenchymal marker slug and a lower expression ofepithelial marker were observed to correlate with tumorgrade presence of lymphnodemetastases and advanced stagebreast cancer The follow-up survival data clearly linked lowE-cadherin and high vimentinslug to poor prognosis andtumor recurrence

Our work with autocrine motility factor (AMF) inthe metastasis of breast cancer cells has highlighted animportant mechanistic involvement of EMT [70] AMF alsoknown as phosphoglucose isomerase has been linked topoor patient survival and tumor recurrence [71] An earlierreport suggested a downregulation of E-cadherin in AMF-expressing cells and conversely its upregulation in AMF-silenced cells which was consistent with EMT [72] Weobserved that the EMT induction in AMF-expressing cellswas marked by not only a downregulation of epithelialmarker E-cadherin but also by the induction ofmesenchymalmarkers vimentin ZEB-1 and ZEB-2 and all this involveda mechanistic involvement of miRNAs [70] The process ofEMT is evidently complex which often involves multiplefactorsmdashthere are multiple determinantsmolecular markersof epithelial versus mesenchymal phenotype all of whichmight not be found to be altered under all experimentalconditions Also the markers of EMT are interregulated aswell as regulated by other factors such as miRNAs [73]There are many levels of regulation the details of which areonly beginning to emerge Table 1 lists the various molecularmarkers of EMT that have been associated with breast cancerrecurrence

43 1205731-Integrin The recognition of 1205731-integrin in recur-rence of breast cancer originates from the observation that

a majority of cancers including breast cancer enter a state ofdormancy Tumor dormancy is the stage where cancer cellsafter primary cancer intervention and apparent treatmententer a state wherein they virtually go undetected waitingfor right time and conditions to trigger cancer recurrence[8] Clinical proof for existence of tumor dormancy wasprovided in a study that looked for circulating tumor cellsin 36 dormancy patients [74] Of these 36 patients 13 hadcirculating tumor cells 7 to 22 years after mastectomy butthe patients had no evidence of clinical disease suggestingthat tumor cells do undergo dormancy and they remainin systemic circulation Incidentally circulating tumor cellshave themselves been proposed as molecular determinantsof breast cancer recurrence [75] The dormant cells arerefractory to chemotherapy as well as radiation therapy [7677] A major challenge in our understanding of this wholeprocess is the elucidation of mechanism(s) by which thedormant tumor cells eventually decide to leave dormancyand form tumors at distant sites leading to recurrence ofdisease many years after the initial ldquosuccessfulrdquo treatmentof breast cancer 1205731-integrin is one molecular factor thathas been proposed to play an important role in the switchfrom dormant state to that of metastatic progression indifferent human cancers [78] including breast cancer [7980] These mechanistic investigations revealed interactionsof 1205731-integrin with several factors such as focal adhesionkinase (FAK) urokinase-type plasminogen activator receptor(uPAR) extracellular signal-regulated kinase (ERK) and epi-dermal growth factor receptor (EGFR) all of which influencetumor microenvironment and have been implicated in breastcancer progression [81ndash88] It is therefore not surprisingthat the inhibitors of 1205731-integrin have shown promise inclinical trials for prevention of breast cancer metastasis andrecurrence [78]

44 Notch Signaling Notch signaling is associated withnormal developmental processes [89 90] and the loss ofNotch signaling leads to embryonic lethality [91] Activationof Notch signaling is believed to be a ldquohallmarkrdquo of aggres-sive cancers There are four known Notch-family receptorsin humans Notch-1 Notch-2 Notch-3 and Notch-4 Theligands for Notch receptors identified in mammalian cellsare Jagged-1 Jagged-2 Delta-like 1 Delta-like 3 and Delta-like 4 Binding of Notch ligands to their receptors initiatesa proteolytic cascade resulting in the release of intracellularpart of Notch which translocates to nucleus and regulates thetranscription of several target genes [92]

The ligand Jagged-1 was evaluated as a determinant ofbreast tumor recurrence in a study that examined 887 samplesfrom a prospectively accrued cohort [93] Reduced disease-free survival was used as a criterion to propose the roleof Jagged-1 as a factor for breast tumor recurrence It wasobserved that the tumors expressing high levels of Jagged-1mRNA and protein correlated with reduced disease-free sur-vival Interestingly mRNA levels of Jagged-1 alone were not avery reliable factor in determining poor disease-free survivalparticularly when adjusted for the presenceabsence of otherbreast cancer biomarkers These observations suggested a

6 ISRN Oncology

functional role of active Jagged-1 in determining the aggres-sive phenotype of recurrent breast cancers A correlationof Jagged-1 with ERPR negativity was also observed whichwas further confirmed by another study [94] which reportedhigher Jagged-1 levels in triple negative breast cancer cellscompared to ER-positive and HER2-expressing cells Thislatter study [94] took a genomics approach to list downstreamtargets of Jagged-1 and focused on cell cycle regulatory factorcyclin D1 which was found to be a direct target of Notch-family proteins Notch-1 and Notch-3 as well Both Jagged-1and cyclin D1 levels correlated well with triple negative breastcancers and Jagged-1 was found to play an important role inbinding of Notch-1 to cyclin D1 promoter an event necessaryfor cell cycle progression

As discussed earlier in this paper there is a direct con-nection between CSCs and tumor recurrence In a study thatwas designed to investigate the role of Notch family in stem-cell-like phenotype [95] the levels of Notch family receptorswere determined in breast cells that were enriched for breastCSC markers ESA and CD44 In these cells with enrichedCSC markers Notch-1 signaling activity was found to beincreased 4-fold while the Notch-4 signaling activity wasfound to be even higher with 8-fold induction Mechanisticstudies were carried out through downregulation of Notch-1Notch-4 and it was reported that Notch-4 inhibition wasmore robustly associated with downregulation of stem-cellphenotype This and another in vitro study [96] suggesteda role of Notch signaling in breast CSCs A role of Notch-3 in CSC quiescence has also been suggested [97] whichmight be relevant to tumor recurrence because as discussedpreviously quiescence happens to be one of the mechanismsthrough which CSCs evade the cytotoxic effects of anticancerdrugs and radiation therapy In a mouse model of HER2breast cancers [98] inhibition of Notch signaling throughthe use of a 120574-secretase inhibitor MRK-003 was found to killCSCs in vitro as well as in vivo This indicates that Notchsignaling is relevant not only to triple negative breast cancersbut also to HER2-over-expressing breast cancers Recently ithas been reported thatmonoclonal antibodies against Notch-1 have remarkable activity against CSCs [99] which clearlydemonstrates a correlation between Notch signaling and thebreast tumor recurrence through CSC phenotype

In addition to their role in breast tumor recurrencethrough regulation ofCSCsNotch-familymembers have alsobeen linked to uPA signaling which further supports theirability to influence tumor recurrence [100] uPA signaling iselevated in several human cancers [82] and an inhibitionof uPA and its receptor uPAR has been demonstrated byus to result in reduced cell proliferation and invasion ofbreast cancer cells [83] The study by Shimizu et al [100]confirmed an association between Jagged-1 and uPA in thebasal type breast cancer subtype Activation of Notch-1 byJagged-1 was found to result in upregulation of uPA signalingwhich resulted in breast cancer progression

Tumor recurrence is closely related to drug resistance Ina study that explored the possibility of inhibiting Notch sig-naling to overcome trastuzumab resistance [101] it was foundthat combined inhibition of Notch and HER2 signaling path-ways can indeed decrease recurrence rates for breast cancers

that are characterized byHER2 overexpressionHER2 is over-expressed or amplified in 20ndash30 invasive breast cancers[6] and HER2-overexpressing breast cancers are invariablylinked to worse prognosis and poor survival [102] In normaltissues expression of HER2 is low but in breast cancer cellsits expression is so high that there can be up to two millionreceptors on a single cell [102ndash104] Breast cancer cellsmarked by overexpression of HER2 can be effectively tar-geted by HER2-specific therapies Marketed as ldquoHerceptinrdquotrastuzumab is a monoclonal antibody that is very effec-tive in HER2-overexpressing breast cancers Trastuzumabhas unique place in cancer research as this was the firstmonoclonal antibody approved in 1998 for use against asolid tumor Trastuzumab remains a standard of care for thetreatment of HER2-overexpressing breast cancers in adjuvantas well as in metastatic recurrent breast cancer settingsHowever trastuzumab therapy also suffers fromdevelopmentof drug resistance that is resistance against trastuzumab [6]In this regard the study by Pandya et al [101] was assumedto be significant because it suggested that targeted inhibitionof Notch signaling might benefit patients whose tumorshave turned resistant to trastuzumab This study comparedtrastuzumab-sensitive HER2-overexpressing BT474 breastcancer cells with their trastuzumab-resistant counterparts120574-secretase inhibitors LY411575 and MRK-003 were used toinhibit Notch signaling

Collectively these studies seem to indicate that selectivetargeting of Notch signaling can reduce breast cancer tumorrecurrence and increase disease-free survival an idea thatneeds to be further investigated [105 106]

45 Wnt Signaling Wnt family of proteins includes severalglycoproteins that activate various intracellular pathwaysafter binding to transmembrane frizzled receptor familyproteins or to a complex comprising of frizzled and LDLreceptor-related proteins 56 The best studied Wnt pathwaythe Wnt120573-catenin pathway is known as the ldquocanonicalrdquoWnt pathway In the absence of Wnt ligands 120573-cateninis recruited into a destruction complex of adenomatouspolyposis coli and axin which induce the phosphorylationof 120573-catenin through casein kinase and glycogen synthasekinase 3 (GSK3) This leads to ubiquitylation and proteaso-mal degradation of 120573-catenin When Wnt proteins bind tofrizzled disheveled is activatedwhich recruits the destructioncomplex to plasma membrane inhibiting GSK3 and thuspreventing phosphorylation of 120573-catenin 120573-catenin thenaccumulates in the cytoplasm and translocates to the nucleuswhere it activates target genes [107]

Similar to Notch signaling a role of Wnt signaling inbreast tumor recurrence has also been suggested [44 106108] A direct proof was provided through a study on tumorsuppressor Wnt-5a [109] It was found that the expression ofWnt-5a was lost in 78 of the patients with recurrent diseasecompared with only 35 of recurrence-free patients Thisstudy suggested the usefulness of Wnt-family member Wnt-5a as a possible biomarker for breast tumor recurrence with anegative correlation Loss of Wnt-5a significantly increasedmetastases but not the proliferation of breast cancer cells

ISRN Oncology 7

A follow-up study by the same research group [110] cameup with the minimal amino acid sequence that could mimicWnt-5a effects Further evidence in support of a role of Wntsignaling in recurrent and invasive breast cancers came fromthe study on HBP1 the transcriptional repressor of Wntsignaling [111] This study identified a correlation betweeninactivating HBP1 mutations and invasive breast cancersin clinical breast cancer samples The mutations in HBP1rendered them ineffective in suppressingWntwhich results inincreased invasive potential a hypothesis that was also testedby using RNA interference to reduce HBP1 levels Statisticalanalysis on breast cancer patient database revealed a directrelationship between reduced HBP1 levels (or increased Wntsignaling) and increased cancer recurrence Debies et al [112]provided a direct mechanism of activated Wnt signaling thatresulted in breast cancer recurrence after targeted therapy

In a study that looked at Wnt signaling with relation totumor relapse in various subtypes it was determined thatWnt signaling was upregulated in the basal subtype partic-ularly in brain-specific relapse [113] In the triple negativebreast cancer model represented by CRL-2335 and MDA-MB-468 cells inhibition of Wnt signaling by a treatmentregime comprising of cisplatin plus TRAIL was found tobe most effective in inhibiting the CSCs [114] A numberof treatments were compared in this study namely PARPinhibitors paclitaxel docetaxel cisplatin and cisplatin plusTRAIL The involvement of Wnt signaling in the mosteffective treatment suggests its importance in CSC phenotypethat is responsible for breast tumor recurrence Thus itappears that Wnt signaling contributes to CSC phenotypeand additionally is transcriptionally important for the deter-mination of aggressive breast tumors that recur and relapse Arecent report has suggested that Wnt signaling is commonlyactivated in metaplastic breast carcinomas [115] Althoughthese metaplastic carcinomas represent only 1 of totalinvasive breast carcinomas they have a particular high riskof local recurrence

46 Hedgehog Signaling Hedgehog (Hh) pathway is mainlyinvolved in the development of organs in most animals [116]Hh gene was first identified in Drosophila and the threemammalian counterparts Sonic Hedgehog (Shh) DesertHedgehog (Dhh) and Indian Hedgehog (Ihh) were iden-tified later [117] Shh binds to its 12-pass transmembranereceptor Patched resulting in derepression of Smoothened[116ndash118] and leading to the activation of Gli2 in the cyto-plasm Gli2 translocates to the nucleus and regulates thetranscription of Shh-pathway target genes includingGli1 andPatched1

Similar to Notch and Wnt signaling pathways discussedpreviously there is evidence to suggest a correlation betweenHh signaling and tumor recurrence [108 119 120] Forexample in a study [121] that evaluated 279 patients withinvasive breast ductal carcinoma expression ofHhwas foundto be a strong determinant of increased risk of metastasesand breast-cancer-specific deaths all hallmarks of tumorrecurrence and lethal disease High epithelial Hh ligand andhigh stromal Gli1 were observed to be crucial predictors

of overall survival The ligand Shh has also been shownto increase vascularity and angiogenesis in a novel VEGF-independent pathway in vitro as well as in clinical samplesfrombreast cancer patients [122] Angiogenesis and increasedvascularity play an important role in cancer metastases andbone metastases are very common in advanced breast cancerpatients There is evidence to suggest a role of Hh signalingin altering the bone microenvironment making it suitablefor homing of breast cancer cells [123] It has therefore beensuggested that selective targeting of Hh signaling might bebeneficial in preventing bone metastases of breast cancers[124 125]

As with other potential biomarkers of tumor recurrencediscussed previously there has been an interest in evaluatingHh signaling members in different breast cancer subtypes aswell In one such study [126] it was observed that Gli1 expres-sion correlated well with basal breast cancer subtype and thepatients with high nuclear expression of Gli1 had significantlyreduced survival time In another study that focused ontriple negative breast cancers [127] it was observed thatSmoothened and Gli1 were significantly upregulated in triplenegative breast cancers as compared to the other breastcancer subtypes The individual members of hedgehog sig-naling Shh Gli1 and Smoothened were found to correlatewith increased metastasis and tumor grade while at thesame time Gli1 expression was inversely associated with ERThis histological evidence supports a role of Hh signaling inadvanced breast tumors that relapse In the context of drugresistance and breast tumor recurrence Smoothened andGli1were reported to be significantly upregulated in tamoxifen-resistant derivative of otherwise tamoxifen-sensitive MCF-7andT47Dbreast cancer cells [128]This study also establisheda link between PI3KAkt signaling pathway and the Hhsignaling in the development of tamoxifen-resistant breastcancers

47 miRNAs MicroRNAs (miRNAs) are small (19ndash24 nu-cleotides) noncoding RNA molecules which down-regulategene expression by interacting with sequences located in the31015840 untranslated region (UTR) of target mRNAs resultingin either translational repression or degradation of mRNAs[129] Regulation of oncogenestumor suppressor genes bymiRNAs is now recognized as a key step in the progression ofhuman malignancies [130] and it is dependent on sequencecomplementarities miRNAs largely function via repressionof their target genes therefore if the target gene of amiRNA is an oncogene that particular miRNAwill be tumorsuppressive In contrast an oncogenic miRNA is the onewhose target is a tumor suppressor gene [131] miRNAsrepresent attractive targets for therapy particularly in breastcancer and breast cancer is a very well-studied cancer withregard to evaluation of various microRNAs that might playkey roles in its progression [132ndash135] Multiple reports haveshown that the loss and gain of specificmiRNAs influence theprocesses of invasion andmetastasis of human breast cancers[73 136ndash138]

miR-126 and miR-335 were the early miRNAs connectedwith breast cancer recurrence when it was proposed that

8 ISRN Oncology

the expression of these two miRNAs is lost in a majorityof breast cancer patients who suffer relapse [139] Conse-quently loss of both of these miRNAs is associated withpoor metastasis-free survival This was followed by thesuggestion that miR-31 and miR-34c might be the miRNAsthat are upregulated in recurrent breast tumors [140] Asubsequent study confirmed the downregulation of miR-335in recurrent tumors and this miRNA was identified as arobust inhibitor of tumor reinitiation [141] In a study thatemployed global miRNA together with mRNA expressionprofiling to list miRNAs that might have a prognostic valuein determining distant relapse-free survival several miRNAswere found to be prognostically important in ER-positiveas well as ER-negative breast cancers [142] When matchedfor the mRNA targets the two miRNAs that stood out fortheir putative prognostic value were miR-210 and miR-128aMore recent data has connected miR-92a with better out-come and reduced tumor recurrence [143] and miR-9 withincreased tumor recurrence [144] An interesting observationwas made in a study on miR-34a when its expression wasexamined in 1172 breast tumors [145] First of all it wasdetectable in most of the samples studied The tumors withhigh expression of miR-34a represented aggressive breastcancers but the tumors with lower expression suffered fromsignificantly increased tumor recurrence Thus this miRNApresented a novel and peculiar finding which needs to beexplored further Another miRNA down-regulated in recur-rent breast tumors miR-320 is believed to function throughits regulation of phosphatase and tensin homolog (PTEN)[146]

As discussed before breast cancer frequentlymetastasizesto bone and that metastasis is one of the primary reasons fortumor recurrence Several investigations have been carriedout to uncover the miRNA regulation of breast cancermetastases that might be the reason for tumor relapse Inone such study that focused on bone metastasis of breastcancer miR-21 and miR-181a were found to be enriched inbone metastatic breast cancers leading to poor prognosis[147] This study primarily utilized miRNA microarray todistinguish the miRNA signature between 4 patients whorepresented recurrent breast cancer versus 4 breast cancerpatients without recurrence Later the results were validatedin bone marrow samples from 291 additional patients

In the context of drug resistance and breast cancerrecurrence Bergamaschi andKatzenellenbogen [148] studiedthe tamoxifen-induced induction of 14-3-3120577 which conferstamoxifen resistance leading to cancer relapse The studyrevealed a mechanistic role of miR-451 which was down-regulated by tamoxifen leading to derepression of its target14-3-3120577 The tamoxifen-resistant cells were marked by upreg-ulated 14-3-3120577 and down-regulated miR-451 A more recentstudy has indicated that there is no single miRNA profilepredictive of outcome following tamoxifen treatment [149]This points to the limitations and challenges in the field ofmiRNA research and the need formore robust investigations

EMT and its regulation by miRNAs are not novel infor-mation anymore However a recent study evaluated thisconnection with possible clinical relevance This study founda regulation of mesenchymal marker vimentin by miR-30a

Table 2 miRNAs that influence breast tumor recurrence

miRNA Status in recurrent breast tumors ReferencemiR-9 Upregulated [144]miR-21 Upregulated [147]miR-30a Downregulated [150]miR-31 Upregulated [140]miR-34a Downregulated [145]miR-34c Upregulated [140]miR-92a Downregulated [143]miR-122 Upregulated [151]miR-125b Upregulated [152]miR-126 Downregulated [139]miR-181a Upregulated [147]miR-320 Downregulated [146]miR-335 Downregulated [139 141]miR-451 Downregulated [148]

[150] Since vimentin is associated with EMT and an inva-sive phenotype miR-30a correlated with reduced invasionand breast cancer aggressiveness The clinical importanceof this regulation was revealed with the observation thatbreast cancer patients with reduced levels of miR-30a hadpoor prognosis increased metastases and worse prognosisThis study provided further evidence connecting EMT withincreased breast cancer recurrence

Detection of miRNAs in circulation is a hot topicattracting attention in an attempt to predict the outcome oftherapeutic regime as well as chances of tumor relapse Inone such recent study [151] more than 800 miRNAs wereactually detected in the serum of breast cancer patientsAfter vigorous analyses miR-122 stood out as the miRNAthat was significantly induced in metastatic breast cancerpatients with recurrence Circulating miRNAs have alsobeen evaluated in relation to resistance to chemotherapyand miR-125b expression in circulation has been linked toincreased chemoresistance [152] This knowledge holds a lotof promise particularly for the early stage patients who canbe monitored on a regular basis for the possible chances ofcancer relapsewhich can then be handled clinically at an earlystage Although a significant advancement use of circulatorymiRNAs in clinical prognosis is still in its early stages whichneeds to be developed further [153]

The last few years have seen an exponential increase inthe number of investigations focused on the functionality ofmiRNAs in breast cancer progression There has also beenan interest in studying miRNAs with possible implicationsin predicting breast cancer recurrence Table 2 lists variousmiRNAs that have been shown to relate to recurrence ofbreast cancer The area of research involving miRNAs isrelatively new but has captured the imagination of a largenumber of researchersMore robust investigations are neededto further exploit the potential of these tiny regulatorymolecules

ISRN Oncology 9

5 Therapeutic Options to PreventBreast Cancer Recurrence

The preceding section focused onmany factors that are beingpursued in an attempt to better understand breast cancerrecurrence The ultimate goal of such knowledge will beto utilize it for the development of targeted therapies tospecifically prevent relapse of breast cancer Here is a list ofoptions that are already under investigation(s) The list is notvery exhaustive and is purposely kept so to reflect on thelimited options that are available so as also to avoid beingoverly enthusiastic about the progress beingmade in the field

51 Aromatase Inhibitors As mentioned earlier in this papera subset of breast cancers are marked by expression of estro-gen receptor and such ER-positive breast cancers requireestrogen for their growth and proliferation MCF-7 cellline developed at our Institute (erstwhile called MichiganCancer Foundation MCF) the most widely studied breastcancer cell line in preclinical studies worldwide repre-sents ER-positive breast cancers With an importance ofestrogen in the sustenance of this breast cancer subtypeit becomes logical to block the production of estrogen inaffected breast cancer patients This can be accomplishedby the inhibition of enzyme aromatase that is involved inthe production of estrogen As such aromatase inhibitorsrepresent a class of compoundsanticancer drugs that can beused for their beneficial effects in ER-positive breast cancerpatients [154 155] The common aromatase inhibitors in useinclude those that permanently inhibit aromatase as wellas those whose action is reversible Interestingly naturalanticancer agents such as resveratrol with documented anti-cancer property [156 157] are natural aromatase inhibitors[158]

Metastases to distant organs in the initial 2 years follow-ing surgery are the major reasons for tumor recurrences inbreast cancer patients treated with tamoxifen the targeteddrug against estrogen receptors [159] Data from clinicalstudies have suggested a usefulness of aromatase inhibitorsin preventing early stage distant metastases and therefore ithas been proposed that initial therapy involving adjuvant useof aromatase inhibitors can be beneficial against tumor recur-rence [160 161] For many years a five-year administration oftamoxifen has been the gold standard for endocrine therapyin ER-responsive breast cancer patients and this notion isincreasingly being challengedwith the inclusion of aromataseinhibitors in the initial years of therapy [162]

As with most therapies the use of aromatase inhibitorsposes its own challenges mainly in the form of severalpossible side effects and complications which need to bediscussed upfront [163] In particular aromatase inhibitorsaffect cardiovascular and bone health which needs to bemonitored throughout the course of therapy Estrogen actionis important for normal bone mineral density and thereforeuse of aromatase inhibitors can severely compromise bonemineral density in patients Bone fracture risk assessmentshould be an important component of care for patientsreceiving aromatase inhibitors [164] Therefore aromatase

inhibitors should be considered for use only in ER-positivepatients with high risk of recurrence as opposed to the post-menopausal patients with relatively lower risks of recurrentmetastatic disease [165] The apparent toxicity of aromataseinhibitors promptedAmir et al [166] to evaluate the existenceof improved disease-free survival without any significantoverall survival In this systemic review of seven trials with30023 patients it was found that a 5-year use of aromataseinhibitors was associated with actual increased odds ofdeath that were nonsignificant Such 5-year use of aromataseinhibitors correlated with reduced recurrence compared to5 years of tamoxifen administration or the switching fromtamoxifen to aromatase inhibitors The analyses suggestedthat cumulative toxicity of aromatase inhibitors might berelevant to lack of overall survival and the switch therapyinvolving administration of tamoxifen for 2-3 years followedby a switch to aromatase inhibitors for subsequent 2-3 yearsmight be a more rational and balanced approach

52 Bisphosphonates Bone represents a major site of metas-tasis in breast cancer patients Metastases to bone disrupt thenormal bone homeostasis resulting in loss of bone integrityand function In addition to direct metastasis of cancer tobone several other factors also influence bone integrity andthese include chemotherapy-induced effects as well as theconsequences of aromatase inhibitors use [167 168] It hasbeen suggested that the breast cancer patients are at particularrisk of bone fracture because of administration of aromataseinhibitors [168] This means that the health of skeletal systemof breast cancer survivors is a unique challenge that needsattention Towards this end the use of bisphosphonates toprevent bone-metastases-related effects has been suggestedand it is believed that approximately half of the patients takingbisphosphonates report significant improvement in pain [167169] This has resulted in a recommendation that breastcancer patients with confirmed bone metastases should startreceiving bisphosphonates right from the time of diagnosis[170]

Bisphosphonates improve the quality of life of bonemetastatic breast cancer patients dealing with underlyingpain but there is also evidence to suggest that early admin-istration of bisphosphonates can actually help reduce theinstance of metastasis to bone [171] Several preclinical aswell as clinical studies have established the ability of bis-phosphonates to prevent metastases of breast cancer [172ndash175] The use of bisphosphonates has been shown to reduceproliferation migration invasion and metastasis of breastcancer cells in many of these studies As a direct proof insupport of the ability of bisphosphonates to reduce breastcancer recurrence several clinical trials have demonstratedsuch ability of bisphosphonates clodronate and zoledronicacid [176] A number of studies support an associationbetween bisphosphonates administration and lower breastcancer incidencerecurrence [176]

53 Natural Compounds A majority of therapeutic regimesrely on anticancer agentscompounds that most of the timehave very specific targets These therapies seem to work

10 ISRN Oncology

initially however as mentioned in the very beginning ofthis paper a lot of such therapies become useless with thepassage of time Targeted drugs take care of their intendedtargets very effectively but with the continued administra-tion tumor cells reduce their dependency on the targeted fac-torpathways and switch to an alternative survival pathwayIt has therefore been advocated that multitargeted cancertherapy should result in prolonged disease-free survivalMultitargeted therapy has its own shortcomings Most of thetargeted therapies come with their own associated toxicitiesThrow in a mixture of such agents and we can end up withenormous side effects These observations have come in theway of more detailed clinical studies aimed at combininganticancer drugs One alternative is the use of natural agentsthe compounds that exist in nature as constituents of variousedible fruitsvegetables A number of such compounds arepleiotropic that is they target multiple signaling pathways[177ndash181] Additionally being part of normal human dietthey usually have considerably reduced toxic effects whencompared to conventional therapeutics

As direct evidence connecting natural anticancer com-pounds to reducing breast cancer recurrence soy isoflavoneconsumption has been linked to reduced risk of breast cancerincidence andmore importantly to the reduced risk of breastcancer recurrence [182] CSCs are very crucial to the phe-nomenon of tumor recurrence and several natural anticanceragents such as curcumin sulforaphane isoflavones EGCGand resveratrol have been shown to affect signaling pathwayslike NotchWnt and Shh leading to their action against CSCs[183] EGCG was shown to inhibit Wnt signaling througha regulation of HBP1 transcriptional repressor [184] andknockdownofHBP1was found to result in reduced sensitivityto EGCG treatment

The previous discussion highlights the connectionbetweenCSCs EMT and the various signaling pathways suchas Notch Wnt and Hh that might influence breast cancerrecurrence A number of studies have described a beneficialeffect of natural compounds through the modulation ofthese factors [181 185ndash190] but a detailed discussion onthese topics is beyond the scope of this paper and readersare encouraged to refer to the referenced articles The recentliterature has added miRNAs to the list of factors that mayinfluence breast cancer recurrence and there is evidencein the literature to suggest a regulatory effect of naturalcompounds on miRNAs as well [191ndash194]

6 Conclusions and Perspective

The cause(s) of breast cancer recurrence and the possiblestrategies to prevent it remain elusive There is an urgentneed to decipher the complex relationship between individualcomponents leading to recurrence but also to then come upwith effective therapies with minimal toxicity Talking aboutcomplex interrelationships there is enough evidence to linkEMT with NotchWntHh signaling [112 183 194 195] EMTwith CSCs [51 52 187] EMT with miRNAs [73 194 196]NotchWntHh signaling with CSCs [99 105 119 177 183]and CSCs with miRNAs [193 196] All this points to a

CSCs

EMT

Signaling pathways(NotchWntHh)

miRNAs

Figure 3 Complex interplay of factors that influence breast cancerrecurrence The various molecular determinants of tumor recur-rence are very intricately connected and interregulated making itdifficult to establish a hierarchical sense

hotchpotch of cellularphysiological events that have beenobserved in breast cancers with recurrence (Figure 3) Whileindividual reports have verified the existence of one or moreof these it is essential to point out that we are far from ascer-taining the causative reason for breast cancer recurrenceThehierarchy of these factors is not at all understood With theintricate relationship between these individual factors it willalways be difficult to guess what happens first a breast cancerrecurrence equivalent of ldquochicken or the eggrdquo

Breast cancer mortality is largely related to either resis-tance to therapies or metastases to distant organs all ofwhich contribute to recurrence One factor that has greatlyhampered our progress in the field is the absence of anyacceptable model for the study of tumor recurrence [197]The in vitro studies are so often not ldquophysiologically relevantrdquowhile the in vivo clinical observations are either so variableor simply inconclusive For a meaningful study it is vital tofoster a healthy collaboration between the basic scientists andclinical investigators Breast cancer recurrence is too complexa problem to be understood entirely through laboratoryinvestigations or the clinical observations alone The wealthof literature that has accumulated in the past several yearsis a good start Now is the time for a concerted effort inorder to provide a direction to the ongoing investigationsthrough more meaningful exhaustive collaborative projectsthat culminate in well-designed clinical trials This alone canchange the lives of scores of women suffering with recurrentaggressive breast cancers with uncertain future at least for thetime being

References

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[2] ldquoNCIrsquos SEER cancer statistics reviewrdquo 2012 httpseercancergovcsr1975 2009 pops09results mergedsect 04 breastpdf

[3] E P Simard S Fedewa JMa R Siegel andA Jemal ldquoWideningsocioeconomic disparities in cervical cancer mortality among

ISRN Oncology 11

women in 26 states 1993ndash2007rdquo Cancer vol 118 pp 5110ndash51162012

[4] J Tang A Ahmad and F H Sarkar ldquoThe complexities of racialdisparity in breast cancerrdquo in Breast CancerMetastasis andDrugResistance A Ahmad Ed pp 35ndash46 Springer New York NYUSA 2012

[5] A Ahmad ZWang R Ali et al ldquoCell cycle regulatory proteinsin breast cancer molecular determinants of drug resistance andtargets for anticancer therapiesrdquo inBreast Cancer Cells R L AftEd pp 113ndash130 InTech 2012

[6] A Ahmad and F H Sarkar ldquoCurrent understanding of drugresistancemechanisms and therapeutic targets inHER2 overex-pressing breast cancersrdquo in Breast Cancer Metastasis and DrugResistance A Ahmad Ed pp 261ndash274 Springer NewYorkNYUSA 2012

[7] S E Moody D Perez T C Pan et al ldquoThe transcriptionalrepressor Snail promotes mammary tumor recurrencerdquo CancerCell vol 8 no 3 pp 197ndash209 2005

[8] P E Goss and A F Chambers ldquoDoes tumour dormancy offera therapeutic targetrdquoNature Reviews Cancer vol 10 no 12 pp871ndash877 2010

[9] T Saphner D C Tormey and R Gray ldquoAnnual hazard rates ofrecurrence for breast cancer after primary therapyrdquo Journal ofClinical Oncology vol 14 no 10 pp 2738ndash2746 1996

[10] ldquoEffects of chemotherapy and hormonal therapy for early breastcancer on recurrence and 15-year survival an overview of therandomised trialsrdquo Lancet vol 365 pp 1687ndash1717 2005

[11] S Y Wang T Shamliyan B A Virnig and R Kane ldquoTumorcharacteristics as predictors of local recurrence after treatmentof ductal carcinoma in situ a meta-analysisrdquo Breast CancerResearch and Treatment vol 127 no 1 pp 1ndash14 2011

[12] R D Chacon and M V Costanzo ldquoTriple-negative breastcancerrdquo Breast Cancer Research vol 12 no 2 article S3 2010

[13] K E Huber L A Carey and D E Wazer ldquoBreast cancermolecular subtypes in patients with locally advanced diseaseimpact on prognosis patterns of recurrence and response totherapyrdquo Seminars in Radiation Oncology vol 19 no 4 pp 204ndash210 2009

[14] M De Boer J A A M Van Dijck P Bult G F Borm and VC G Tjan-Heijnen ldquoBreast cancer prognosis and occult lymphnode metastases isolated tumor cells and micrometastasesrdquoJournal of the National Cancer Institute vol 102 no 6 pp 410ndash425 2010

[15] L R Cavalli ldquoMolecular markers of breast axillary lymph nodemetastasisrdquo Expert Review of Molecular Diagnostics vol 9 no5 pp 441ndash454 2009

[16] J Ruiterkamp andM F Ernst ldquoThe role of surgery inmetastaticbreast cancerrdquo in European Journal of Cancer vol 47 supple-ment 3 pp S6ndashS22 2011

[17] M Gieni R Avram L Dickson et al ldquoLocal breast cancerrecurrence after mastectomy and immediate breast reconstruc-tion for invasive cancer a meta-analysisrdquo Breast vol 21 pp230ndash236 2012

[18] B Fisher S Anderson C K Redmond N Wolmark D LWickerham and W M Cronin ldquoReanalysis and results after12 years of follow-up in a randomized clinical trial comparingtotal mastectomy with lumpectomy with or without irradiationin the treatment of breast cancerrdquo The New England Journal ofMedicine vol 333 no 22 pp 1456ndash1461 1995

[19] J A Jacobson D N Danforth K H Cowan et al ldquoTen-yearresults of a comparison of conservation with mastectomy in

the treatment of stage I and II breast cancerrdquoThe New EnglandJournal of Medicine vol 332 no 14 pp 907ndash911 1995

[20] F van der Leij P H Elkhuizen H Bartelink and M J van deVijver ldquoPredictive factors for local recurrence in breast cancerrdquoSeminars in Radiation Oncology vol 22 pp 100ndash107 2012

[21] N Houssami P MacAskill M L Marinovich et al ldquoMeta-analysis of the impact of surgical margins on local recurrencein women with early-stage invasive breast cancer treated withbreast-conserving therapyrdquo European Journal of Cancer vol 46no 18 pp 3219ndash3232 2010

[22] S Darby P McGale C Correa et al ldquoEffect of radiotherapyafter breast-conserving surgery on 10-year recurrence and 15-year breast cancer death meta-analysis of individual patientdata for 10 801 women in 17 randomised trialsrdquo Lancet vol 378pp 1707ndash1716 2011

[23] A J Lowery M R Kell R W Glynn M J Kerin and K JSweeney ldquoLocoregional recurrence after breast cancer surgerya systematic review by receptor phenotyperdquo Breast CancerResearch and Treatment vol 133 pp 831ndash841 2012

[24] D Holzel R T Emeny and J Engel ldquoTrue local recurrences donot metastasizerdquo Cancer Metastasis Reviews vol 30 no 2 pp161ndash176 2011

[25] X Meng J Zhong S Liu M Murray and A M Gonzalez-Angulo ldquoA new hypothesis for the cancer mechanismrdquo Cancerand Metastasis Reviews vol 31 pp 247ndash268 2012

[26] L Lacerda L Pusztai andW AWoodward ldquoThe role of tumorinitiating cells in drug resistance of breast cancer implicationsfor future therapeutic approachesrdquo Drug Resistance Updatesvol 13 no 4-5 pp 99ndash108 2010

[27] S PMcDermott andM SWicha ldquoTargeting breast cancer stemcellsrdquoMolecular Oncology vol 4 no 5 pp 404ndash419 2010

[28] A Sanguinetti G Bistoni and N Avenia ldquoStem cells and breastcancer wherewe are A concise review of literaturerdquoGChir vol32 pp 438ndash446 2011

[29] M Rahman L Deleyrolle V Vedam-Mai H Azari M Abd-El-Barr and B A Reynolds ldquoThe cancer stem cell hypothesisfailures and pitfallsrdquo Neurosurgery vol 68 no 2 pp 531ndash5452011

[30] M Baumann M Krause and R Hill ldquoExploring the role ofcancer stem cells in radioresistancerdquo Nature Reviews Cancervol 8 no 7 pp 545ndash554 2008

[31] L Wei T T Liu H H Wang et al ldquoHsp27 participates in themaintenance of breast cancer stem cells through regulation ofepithelial-mesenchymal transition and nuclear factor-kappa BrdquoBreast Cancer Research vol 13 article R101 2011

[32] A Ahmad Y Li B Bao and F H Sarkar ldquoResistance and DNArepair mechanisms of cancer stem cells potential moleculartargets for therapyrdquo in DNA Repair of Cancer Stem Cells LA Mathews S M Cabarcas and E M Hurt Eds pp 33ndash52Springer New York NY USA 2012

[33] MMGottesman T Fojo and S E Bates ldquoMultidrug resistancein cancer role of ATP-dependent transportersrdquoNature ReviewsCancer vol 2 no 1 pp 48ndash58 2002

[34] M Dean ldquoABC transporters drug resistance and cancer stemcellsrdquo Journal ofMammary Gland Biology and Neoplasia vol 14no 1 pp 3ndash9 2009

[35] K Ueda C Cardarelli M M Gottesman and T PastanldquoExpression of a full-length cDNA for the human rsquoMDR1rsquo geneconfers resistance to colchicine doxorubicin and vinblastinerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 84 no 9 pp 3004ndash3008 1987

12 ISRN Oncology

[36] C W Scharenberg M A Harkey and B Torok-Storb ldquoTheABCG2 transporter is an efficient Hoechst 33342 efflux pumpand is preferentially expressed by immature human hematopoi-etic progenitorsrdquo Blood vol 99 no 2 pp 507ndash512 2002

[37] M Kim H Turnquist J Jackson et al ldquoThe multidrug resis-tance transporter ABCG2 (breast cancer resistance protein 1)effluxes Hoechst 33342 and is overexpressed in hematopoieticstem cellsrdquo Clinical Cancer Research vol 8 no 1 pp 22ndash282002

[38] H Lou and M Dean ldquoTargeted therapy for cancer stem cellsthe patched pathway and ABC transportersrdquo Oncogene vol 26no 9 pp 1357ndash1360 2007

[39] Y An andWMOngkeko ldquoABCG2 the key to chemoresistancein cancer stem cellsrdquo Expert Opinion on Drug Metabolism andToxicology vol 5 no 12 pp 1529ndash1542 2009

[40] A Elliot J Adams and M Al-Hajj ldquoThe ABCs of cancer stemcell drug resistancerdquo IDrugs vol 13 no 9 pp 632ndash635 2010

[41] K Sampieri and R Fodde ldquoCancer stem cells and metastasisrdquoSeminars in Cancer Biology vol 22 pp 187ndash193 2012

[42] A J Fridriksdottir O W Petersen and L Ronnov-JessenldquoMammary gland stem cells current status and future chal-lengesrdquoThe International Journal of Developmental Biology vol55 pp 719ndash729 2011

[43] S Badve and H Nakshatri ldquoBreast-cancer stem cells-beyondsemanticsrdquoThe Lancet Oncology vol 13 pp e43ndashe48 2012

[44] C E Eyler and J N Rich ldquoSurvival of the fittest cancer stemcells in therapeutic resistance and angiogenesisrdquo Journal ofClinical Oncology vol 26 no 17 pp 2839ndash2845 2008

[45] H Korkaya S Liu and M S Wicha ldquoBreast cancer stemcells cytokine networks and the tumor microenvironmentrdquoThe Journal of Clinical Investigation vol 121 pp 3804ndash38092011

[46] F Schmitt S Ricardo A F Vieira M R Dionisio and JParedes ldquoCancer stem cell markers in breast neoplasias theirrelevance and distribution in distinct molecular subtypesrdquoVirchows Archiv vol 460 pp 545ndash553 2012

[47] M A Velasco-Velazquez N Homsi M De La Fuente and RG Pestell ldquoBreast cancer stem cellsrdquo The International Journalof Biochemistry amp Cell Biology vol 44 pp 573ndash577 2012

[48] G J Prudrsquohomme ldquoCancer stem cells and novel targets forantitumor strategiesrdquo Current Pharmaceutical Design vol 18pp 2838ndash2849 2012

[49] M P Ablett J K Singh and R B Clarke ldquoStem cells in breasttumours are they ready for the clinicrdquo European Journal ofCancer vol 48 pp 2104ndash2116 2012

[50] Y Yu G Ramena and R C Elble ldquoThe role of cancer stemcells in relapse of solid tumorsrdquo Frontiers in Bioscience vol 4pp 1528ndash1541 2012

[51] B G Hollier K Evans and S A Mani ldquoThe epithelial-to-mesenchymal transition and cancer stem cells a coalitionagainst cancer therapiesrdquo Journal of Mammary Gland Biologyand Neoplasia vol 14 no 1 pp 29ndash43 2009

[52] C Raimondi W Gianni E Cortesi and P Gazzaniga ldquoCancerstem cells and epithelial-mesenchymal transition revisitingminimal residual diseaserdquo Current Cancer Drug Targets vol 10no 5 pp 496ndash508 2010

[53] B Dave V Mittal N M Tan and J C Chang ldquoEpithelial-mesenchymal transition cancer stem cells and treatment resis-tancerdquo Breast Cancer Research vol 14 article 202 2012

[54] J J Christiansen and A K Rajasekaran ldquoReassessing epithelialto mesenchymal transition as a prerequisite for carcinoma

invasion and metastasisrdquo Cancer Research vol 66 no 17 pp8319ndash8326 2006

[55] J P Thiery ldquoEpithelial-mesenchymal transitions in tumourprogressionrdquo Nature Reviews Cancer vol 2 pp 442ndash454 2002

[56] Z Wang Y Li and F H Sarkar ldquoSignaling mechanism(s) ofreactive oxygen species in epithelial-mesenchymal transitionreminiscent of cancer stem cells in tumor progressionrdquo CurrentStem Cell Research andTherapy vol 5 no 1 pp 74ndash80 2010

[57] F H Sarkar Y Li Z Wang and D Kong ldquoPancreatic cancerstem cells and EMT in drug resistance andmetastasisrdquoMinervaChirurgica vol 64 no 5 pp 489ndash500 2009

[58] H J Hugo R Wafai T Blick E W Thompson and D FNewgreen ldquoStaurosporine augments EGF-mediated EMT inPMC42-LA cells through actin depolymerisation focal con-tact size reduction and Snail1 inductionmdasha model for cross-modulationrdquo BMC Cancer vol 9 article 235 2009

[59] J G H van Nes E M de Kruijf H Putter et al ldquoCo-expression of SNAIL and TWIST determines prognosis inestrogen receptor-positive early breast cancer patientsrdquo BreastCancer Research and Treatment vol 133 pp 49ndash59 2012

[60] D D Tran C A Corsa H Biswas R L Aft and G DLongmore ldquoTemporal and spatial cooperation of Snail1 andTwist1 during epithelial-mesenchymal transition predicts forhuman breast cancer recurrencerdquo Molecular Cancer Researchvol 9 pp 1644ndash1657 2011

[61] J E Kwon W H Jung and J S Koo ldquoMolecules involvedin epithelial-mesenchymal transition and epithelial-stromalinteraction in phyllodes tumors implications for histologicgrade and prognosisrdquo Tumor Biology vol 33 pp 787ndash798 2012

[62] T Imamura A Hikita and Y Inoue ldquoThe roles of TGF-betasignaling in carcinogenesis and breast cancermetastasisrdquo BreastCancer vol 19 pp 118ndash124 2012

[63] M A Taylor J G Parvani and W P Schiemann ldquoThepathophysiology of epithelial-mesenchymal transition inducedby transforming growth factor-120573 in normal and malignantmammary epithelial cellsrdquo Journal of Mammary Gland Biologyand Neoplasia vol 15 no 2 pp 169ndash190 2010

[64] M Romagnoli K Belguise Z Yu et al ldquoEpithelial-to-mesenchymal transition induced by TGF-beta1 is mediated byblimp-1-dependent repression of BMP-5rdquo Cancer Research vol72 pp 6268ndash6278 2012

[65] Z D Lv B Kong J G Li et al ldquoTransforming growthfactor-beta 1 enhances the invasiveness of breast cancer cellsby inducing a Smad2-dependent epithelial-to-mesenchymaltransitionrdquo Oncology Reports vol 29 pp 219ndash225 2013

[66] A Bandyopadhyay L Wang J Agyin et al ldquoDoxorubicin incombination with a small TGF120573 inhibitor a potential noveltherapy for metastatic breast cancer in mouse modelsrdquo PLoSONE vol 5 no 4 article e10365 2010

[67] M K Asiedu J N Ingle M D Behrens D C Radisky and KL Knutson ldquoTGF120573TNF120572-mediated epithelial-mesenchymaltransition generates breast cancer stem cells with a claudin-lowphenotyperdquoCancer Research vol 71 no 13 pp 4707ndash4719 2011

[68] N P Tobin A H Sims K L Lundgren S Lehn and GLandberg ldquoCyclin D1 Id1 and EMT in breast cancerrdquo BMCCancer vol 11 article 417 2011

[69] T Liu X Zhang M Shang et al ldquoDysregulated expression ofSlug vimentin and E-cadherin correlates with poor clinicaloutcome in patients with basal-like breast cancerrdquo Journal ofSurgical Oncology vol 107 no 2 pp 188ndash194 2013

ISRN Oncology 13

[70] A Ahmad A Aboukameel D Kong et al ldquoPhosphoglu-cose isomeraseautocrine motility factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancercellsrdquo Cancer Research vol 71 no 9 pp 3400ndash3409 2011

[71] T Funasaka and A Raz ldquoThe role of autocrine motility factorin tumor and tumormicroenvironmentrdquoCancer andMetastasisReviews vol 26 no 3-4 pp 725ndash735 2007

[72] T Funasaka V Hogan and A Raz ldquoPhosphoglucose iso-meraseautocrine motility factor mediates epithelial and mes-enchymal phenotype conversions in breast cancerrdquo CancerResearch vol 69 no 13 pp 5349ndash5356 2009

[73] A Ahmad A S Ali S Ali Z Wang D Kong and F H SarkarldquoMicroRNAs targets of interest in breast cancer researchrdquo inMicroRNA Expression Detection and Therapeutic Strategies JA Mulligan Ed pp 59ndash78 Nova Publishers New York NYUSA 2011

[74] S Meng D Tripathy E P Frenkel et al ldquoCirculating tumorcells in patients with breast cancer dormancyrdquo Clinical CancerResearch vol 10 no 24 pp 8152ndash8162 2004

[75] E S Lianidou and A Markou ldquoCirculating tumor cells inbreast cancer detection systems molecular characterizationand future challengesrdquoClinical Chemistry vol 57 pp 1242ndash12552011

[76] G N Naumov J L Townson I C MacDonald et al ldquoIneffec-tiveness of doxorubicin treatment on solitary dormant mam-mary carcinoma cells or late-developing metastasesrdquo BreastCancer Research andTreatment vol 82 no 3 pp 199ndash206 2003

[77] D A Gewirtz ldquoAutophagy senescence and tumor dormancy incancer therapyrdquo Autophagy vol 5 no 8 pp 1232ndash1234 2009

[78] D Barkan and A F Chambers ldquobeta1-integrin a potentialtherapeutic target in the battle against cancer recurrencerdquoClinical Cancer Research vol 17 pp 7219ndash7223 2011

[79] D Barkan H Kleinman J L Simmons et al ldquoInhibitionof metastatic outgrowth from single dormant tumor cells bytargeting the cytoskeletonrdquo Cancer Research vol 68 no 15 pp6241ndash6250 2008

[80] D Barkan L H El Touny A M Michalowski et al ldquoMetastaticgrowth from dormant cells induced by a Col-I-enriched fibroticenvironmentrdquo Cancer Research vol 70 no 14 pp 5706ndash57162010

[81] M Luo and J L Guan ldquoFocal adhesion kinase a prominentdeterminant in breast cancer initiation progression and metas-tasisrdquo Cancer Letters vol 289 no 2 pp 127ndash139 2010

[82] K Dass A Ahmad A S Azmi S H Sarkar and F H SarkarldquoEvolving role of uPAuPAR system in human cancersrdquo CancerTreatment Reviews vol 34 no 2 pp 122ndash136 2008

[83] A Ahmad D Kong Z Wang S H Sarkar S Banerjee andF H Sarkar ldquoDown-regulation of uPA and uPAR by 331015840-diindolylmethane contributes to the inhibition of cell growthand migration of breast cancer cellsrdquo Journal of Cellular Bio-chemistry vol 108 no 4 pp 916ndash925 2009

[84] A Ahmad Z Wang D Kong et al ldquoFoxM1 down-regulationleads to inhibition of proliferation migration and invasion ofbreast cancer cells through the modulation of extra-cellularmatrix degrading factorsrdquo Breast Cancer Research and Treat-ment vol 122 no 2 pp 337ndash346 2010

[85] P J Keely ldquoMechanisms by which the extracellular matrix andintegrin signaling act to regulate the switch between tumorsuppression and tumor promotionrdquo Journal ofMammary GlandBiology and Neoplasia vol 16 pp 205ndash219 2011

[86] J A McCubrey L S Steelman W H Chappell et al ldquoRoles ofthe RafMEKERK pathway in cell growth malignant transfor-mation and drug resistancerdquo Biochimica et Biophysica Acta vol1773 no 8 pp 1263ndash1284 2007

[87] S A Eccles ldquoThe epidermal growth factor receptorErb-BHERfamily in normal and malignant breast biologyrdquo The Interna-tional Journal of Developmental Biology vol 55 pp 685ndash6962011

[88] J Foley N K Nickerson S Nam et al ldquoEGFR signalingin breast cancer bad to the bonerdquo Seminars in Cell andDevelopmental Biology vol 21 no 9 pp 951ndash960 2010

[89] S Artavanis-Tsakonas K Matsuno and M E Fortini ldquoNotchsignalingrdquo Science vol 268 no 5208 pp 225ndash232 1995

[90] S Artavanis-Tsakonas M D Rand and R J Lake ldquoNotch sig-naling cell fate control and signal integration in developmentrdquoScience vol 284 no 5415 pp 770ndash776 1999

[91] F Radtke and K Raj ldquoThe role of Notch in tumorigenesisoncogene or tumour suppressorrdquo Nature Reviews Cancer vol3 no 10 pp 756ndash767 2003

[92] W R Gordon D Vardar-Ulu G Histen C Sanchez-Irizarry JC Aster and S C Blacklow ldquoStructural basis for autoinhibitionof Notchrdquo Nature Structural and Molecular Biology vol 14 no4 pp 295ndash300 2007

[93] M Reedijk D Pinnaduwage B C Dickson et al ldquoJAG1expression is associated with a basal phenotype and recurrencein lymph node-negative breast cancerrdquo Breast Cancer Researchand Treatment vol 111 no 3 pp 439ndash448 2008

[94] B Cohen M Shimizu J Izrailit et al ldquoCyclin D1 is a directtarget of JAG1-mediated Notch signaling in breast cancerrdquoBreast Cancer Research and Treatment vol 123 no 1 pp 113ndash124 2010

[95] H Harrison G Farnie S J Howell et al ldquoRegulation ofbreast cancer stem cell activity by signaling through the Notch4receptorrdquo Cancer Research vol 70 no 2 pp 709ndash718 2010

[96] P Grudzien S Lo K S Albain et al ldquoInhibition of notchsignaling reduces the stem-like population of breast cancer cellsand prevents mammosphere formationrdquo Anticancer Researchvol 30 no 10 pp 3853ndash3867 2010

[97] S Kent J Hutchinson A Balboni A Decastro P Cherukuriand J Direnzo ldquoDeltaNp63alpha promotes cellular quiescencevia induction and activation of Notch3rdquo Cell Cycle vol 10 pp3111ndash3118 2011

[98] M Kondratyev A Kreso RMHallett et al ldquoGamma-secretaseinhibitors target tumor-initiating cells in a mouse model ofERBB2 breast cancerrdquo Oncogene vol 31 pp 93ndash103 2012

[99] M Qiu Q Peng I Jiang et al ldquoSpecific inhibition of Notch1signaling enhances the antitumor efficacy of chemotherapy intriple negative breast cancer through reduction of cancer stemcellsrdquo Cancer Letters vol 328 pp 261ndash270 2013

[100] M Shimizu B Cohen P Goldvasser H Berman C Virtanenand M Reedijk ldquoPlasminogen activator uPA is a direct tran-scriptional target of the JAG1-notch receptor signaling pathwayin breast cancerrdquo Cancer Research vol 71 no 1 pp 277ndash2862011

[101] K Pandya K Meeke A G Clementz et al ldquoTargeting bothNotch and ErbB-2 signalling pathways is required for pre-vention of ErbB-2-positive breast tumour recurrencerdquo BritishJournal of Cancer vol 105 pp 796ndash806 2011

[102] D J Slamon G M Clark S G Wong W J Levin AUllrich andW L McGuire ldquoHuman breast cancer correlationof relapse and survival with amplification of the HER-2neuoncogenerdquo Science vol 235 no 4785 pp 182ndash191 1987

14 ISRN Oncology

[103] B C Browne N OrsquoBrien M J Duffy J Crown and NOrsquoDonovan ldquoHER-2 signaling and inhibition in breast cancerrdquoCurrent Cancer Drug Targets vol 9 no 3 pp 419ndash438 2009

[104] T Vu and F X Claret ldquoTrastuzumab updated mechanisms ofaction and resistance in breast cancerrdquo Frontiers in Oncologyvol 2 article 62 2012

[105] M J Simmons R Serra N Hermance and M A KelliherldquoNOTCH1 inhibition in vivo results inmammary tumor regres-sion and reduced mammary tumorsphere forming activity invitrordquo Breast Cancer Res vol 14 article R126 2012

[106] S Gangopadhyay A Nandy P Hor and A MukhopadhyayldquoBreast cancer stem cells a novel therapeutic targetrdquo ClinicalBreast Cancer vol 13 no 1 pp 7ndash15 2013

[107] W J Nelson and R Nusse ldquoConvergence of Wnt 120573-Cateninand Cadherin pathwaysrdquo Science vol 303 no 5663 pp 1483ndash1487 2004

[108] C Karamboulas and L Ailles ldquoDevelopmental signaling path-ways in cancer stem cells of solid tumorsrdquoBiochimBiophys Actavol 1830 no 2 pp 2481ndash2495 2013

[109] M Jonsson JDejmek PO Bendahl andTAndersson ldquoLoss ofWnt-5a protein is associatedwith early relapse in invasive ductalbreast carcinomasrdquo Cancer Research vol 62 no 2 pp 409ndash4162002

[110] A Safholm K Leandersson J Dejmek C K Nielsen BO Villoutreix and T Andersson ldquoA formylated hexapeptideligand mimics the ability of Wnt-5a to impair migration ofhuman breast epithelial cellsrdquo Journal of Biological Chemistryvol 281 no 5 pp 2740ndash2749 2006

[111] K E Paulson K Rieger-Christ M A McDevitt et al ldquoAlter-ations of the HBP1 transcriptional repressor are associated withinvasive breast cancerrdquoCancer Research vol 67 no 13 pp 6136ndash6145 2007

[112] M T Debies S A Gestl J L Mathers et al ldquoTumor escapein a Wnt1-dependent mouse breast cancer model is enabled byp19Arfp53 pathway lesions but not p16Ink4a lossrdquo Journal ofClinical Investigation vol 118 no 1 pp 51ndash63 2008

[113] M Smid Y Wang Y Zhang et al ldquoSubtypes of breast cancershow preferential site of relapserdquoCancer Research vol 68 no 9pp 3108ndash3114 2008

[114] S Yin L Xu S Bandyopadhyay S Sethi and K B ReddyldquoCisplatin and TRAIL enhance breast cancer stem cell deathrdquoInternational Journal of Oncology vol 39 pp 891ndash898 2011

[115] S Rungta andCGKleer ldquoMetaplastic carcinomas of the breastdiagnostic challenges and new translational insightsrdquo Archivesof Pathology amp LaboratoryMedicine vol 136 pp 896ndash900 2012

[116] P W Ingham and A P McMahon ldquoHedgehog signaling inanimal development paradigms and principlesrdquo Genes andDevelopment vol 15 no 23 pp 3059ndash3087 2001

[117] B Z Stanton and L F Peng ldquoSmall-molecule modulators of theSonic Hedgehog signaling pathwayrdquoMolecular BioSystems vol6 no 1 pp 44ndash54 2009

[118] D M Stone M Hynes M Armanini et al ldquoThe tumour-suppressor gene patched encodes a candidate receptor for Sonichedgehogrdquo Nature vol 384 no 6605 pp 129ndash134 1996

[119] J Izrailit and M Reedijk ldquoDevelopmental pathways in breastcancer and breast tumor-initiating cells therapeutic implica-tionsrdquo Cancer Letters vol 317 pp 115ndash126 2012

[120] N B Hassounah T A Bunch and K M McDermott ldquoMolec-ular pathways the role of primary cilia in cancer progressionand therapeutics with a focus on Hedgehog signalingrdquo ClinicalCancer Research vol 18 pp 2429ndash2435 2012

[121] S A OrsquoToole D A Machalek R F Shearer et al ldquoHedgehogoverexpression is associated with stromal interactions andpredicts for poor outcome in breast cancerrdquo Cancer Researchvol 71 no 11 pp 4002ndash4014 2011

[122] L G Harris L K Pannell S Singh R S Samant and L AShevde ldquoIncreased vascularity and spontaneous metastasis ofbreast cancer by hedgehog signaling mediated upregulation ofcyr61rdquo Oncogene vol 31 pp 3370ndash3380 2012

[123] S Das R S Samant and L A Shevde ldquoThe hedgehog pathwayconditions the bonemicroenvironment for osteolyticmetastasisof breast cancerrdquo International Journal of Breast Cancer vol2012 Article ID 298623 2012

[124] S Das J A Tucker S Khullar R S Samant and L A ShevdeldquoHedgehog signaling in tumor cells facilitates osteoblast-enhanced osteolyticmetastasesrdquoPLoSOne vol 7 article e343742012

[125] C M Siddappa M A Watson S G Pillai K Trinkaus TFleming and R Aft ldquoDetection of disseminated tumor cells inthe bone marrow of breast cancer patients using multiplex geneexpression measurements identifies new therapeutic targets inpatients at high risk for the development of metastatic diseaserdquoBreast Cancer Research and Treatment vol 137 no 1 pp 45ndash562013

[126] Y Li W Yang Q Yang and S Zhou ldquoNuclear localizationof GLI1 and elevated expression of FOXC2 in breast canceris associated with the basal-like phenotyperdquo Histology andHistopathology vol 27 pp 475ndash484 2012

[127] Y Tao J Mao Q Zhang and L Li ldquoOverexpression ofHedgehog signaling molecules and its involvement in triple-negative breast cancerrdquo Oncology Letters vol 2 no 5 pp 995ndash1001 2011

[128] B Ramaswamy Y Lu K Y Teng et al ldquoHedgehog signaling isa novel therapeutic target in tamoxifen-resistant breast canceraberrantly activated by PI3KAKT pathwayrdquo Cancer Researchvol 72 pp 5048ndash5059 2012

[129] R Garzon M Fabbri A Cimmino G A Calin and C MCroce ldquoMicroRNA expression and function in cancerrdquo Trendsin Molecular Medicine vol 12 no 12 pp 580ndash587 2006

[130] C M Croce ldquoCauses and consequences of microRNA dysreg-ulation in cancerrdquo Nature Reviews Genetics vol 10 no 10 pp704ndash714 2009

[131] S K Shenouda and S K Alahari ldquoMicroRNA function in can-cer oncogene or a tumor suppressorrdquo Cancer and MetastasisReviews vol 28 no 3-4 pp 369ndash378 2009

[132] A J Lowery N Miller R E McNeill and M J KerinldquoMicroRNAs as prognostic indicators and therapeutic targetspotential effect on breast cancer managementrdquo Clinical CancerResearch vol 14 no 2 pp 360ndash365 2008

[133] B D Adams I K Guttilla and B A White ldquoInvolvementof MicroRNAs in breast cancerrdquo Seminars in ReproductiveMedicine vol 26 no 6 pp 522ndash536 2008

[134] M Shi and N Guo ldquoMicroRNA expression and its implicationsfor the diagnosis and therapeutic strategies of breast cancerrdquoCancer Treatment Reviews vol 35 no 4 pp 328ndash334 2009

[135] D R Hurst M D Edmonds and D RWelch ldquoMetastamir thefield of metastasis-regulatory microRNA is spreadingrdquo CancerResearch vol 69 no 19 pp 7495ndash7498 2009

[136] S M Khoshnaw E A Rakha T M Abdel-Fatah et al ldquoLossof Dicer expression is associated with breast cancer progressionand recurrencerdquo Breast Cancer Research and Treatment vol 135pp 403ndash413 2012

ISRN Oncology 15

[137] L Li X Xie J Luo et al ldquoTargeted expression of miR-34a usingthe T-VISA system suppresses breast cancer cell growth andinvasionrdquoMolecular Therapy vol 20 pp 2326ndash2334 2012

[138] J Tang A Ahmad and F H Sarkar ldquoThe role of microRNAs inbreast cancer migration invasion andmetastasisrdquo InternationalJournal of Molecular Sciences vol 13 pp 13414ndash13437 2012

[139] S F Tavazoie C Alarcon T Oskarsson et al ldquoEndogenoushuman microRNAs that suppress breast cancer metastasisrdquoNature vol 451 no 7175 pp 147ndash152 2008

[140] S Pavlides A Tsirigos G Migneco et al ldquoThe autophagictumor stroma model of cancer role of oxidative stress andketone production in fueling tumor cell metabolismrdquoCell Cyclevol 9 no 17 pp 3485ndash3505 2010

[141] K J Png M Yoshida X H F Zhang et al ldquoMicroRNA-335inhibits tumor reinitiation and is silenced through genetic andepigenetic mechanisms in human breast cancerrdquo Genes andDevelopment vol 25 no 3 pp 226ndash231 2011

[142] F M Buffa C Camps L Winchester et al ldquomicroRNA-associated progression pathways and potential therapeutic tar-gets identified by integrated mRNA and microRNA expressionprofiling in breast cancerrdquo Cancer Research vol 71 pp 5635ndash5645 2011

[143] S Nilsson C Moller K Jirstrom et al ldquoDownregulation ofmiR-92a is associated with aggressive breast cancer features andincreased tumour macrophage infiltrationrdquo PLoS One vol 7article e36051 2012

[144] X Zhou C Marian K H Makambi et al ldquoMicroRNA-9 aspotential biomarker for breast cancer local recurrence andtumor estrogen receptor statusrdquo PLoS One vol 7 article e390112012

[145] H Peurala D Greco T Heikkinen et al ldquoMiR-34a expressionhas an effect for lower risk of metastasis and associates withexpression patterns predicting clinical outcome in breast can-cerrdquo PLoS One vol 6 article e26122 2011

[146] A Bronisz J Godlewski J A Wallace et al ldquoReprogrammingof the tumour microenvironment by stromal PTEN-regulatedmiR-320rdquo Nature Cell Biology vol 14 pp 159ndash167 2012

[147] D Ota K Mimori T Yokobori et al ldquoIdentification ofrecurrence-related microRNAs in the bone marrow of breastcancer patientsrdquo International Journal of Oncology vol 38 no4 pp 955ndash962 2011

[148] A Bergamaschi and B S Katzenellenbogen ldquoTamoxifen down-regulation of miR-451 increases 14-3-3zeta and promotes breastcancer cell survival and endocrine resistancerdquoOncogene vol 31pp 39ndash47 2012

[149] M B Lyng A V Laenkholm R Sokilde K H Gravgaard TLitman and H J Ditzel ldquoGlobal microRNA expression pro-filing of high-risk ER+ breast cancers from patients receivingadjuvant tamoxifen mono-therapy a DBCG studyrdquo PLoS Onevol 7 article e36170 2012

[150] C W Cheng H W Wang C W Chang et al ldquoMicroRNA-30a inhibits cell migration and invasion by downregulatingvimentin expression and is a potential prognostic marker inbreast cancerrdquo Breast Cancer Research and Treatment vol 134pp 1081ndash1093 2012

[151] XWuG Somlo Y Yu et al ldquoDe novo sequencing of circulatingmiRNAs identifies novel markers predicting clinical outcomeof locally advanced breast cancerrdquo Journal of TranslationalMedicine vol 10 article 42 2012

[152] H Wang G Tan L Dong et al ldquoCirculating MiR-125b as amarker predicting chemoresistance in breast cancerrdquo PLoS Onevol 7 article e34210 2012

[153] V J Cookson M A Bentley B V Hogan et al ldquoCirculatingmicroRNA profiles reflect the presence of breast tumours butnot the profiles of microRNAs within the tumoursrdquo CellularOncology vol 35 pp 301ndash308 2012

[154] H T Mouridsen P Loslashnning M W Beckmann et al ldquoUseof aromatase inhibitors and bisphosphonates as an anticancertherapy in postmenopausal breast cancerrdquo Expert Review ofAnticancer Therapy vol 10 no 11 pp 1825ndash1836 2010

[155] E C Yiannakopoulou ldquoPharmacogenomics of breast cancertargeted therapy focus on recent patentsrdquo Recent Patents onDNA amp Gene Sequences vol 6 pp 33ndash46 2012

[156] A Ahmad A S Farhan S Singh and S M Hadi ldquoDNAbreakage by resveratrol and Cu(II) reaction mechanism andbacteriophage inactivationrdquo Cancer Letters vol 154 no 1 pp29ndash37 2000

[157] A Ahmad F A Syed S Singh and S M Hadi ldquoProoxidantactivity of resveratrol in the presence of copper ionsMutagenic-ity in plasmid DNArdquo Toxicology Letters vol 159 no 1 pp 1ndash122005

[158] S I Khan J Zhao I A Khan L A Walker and A K Das-mahapatra ldquoPotential utility of natural products as regulatorsof breast cancer-associated aromatase promotersrdquo ReproductiveBiology and Endocrinology vol 9 article 91 2011

[159] J C Doughty ldquoWhen to start an aromatase inhibitor now orlaterrdquo Journal of Surgical Oncology vol 103 no 7 pp 730ndash7382011

[160] E Bria P Carlini F Cuppone V Vaccaro M Milella and FCognetti ldquoEarly recurrence risk aromatase inhibitors versustamoxifenrdquo Expert Review of Anticancer Therapy vol 10 no 8pp 1239ndash1253 2010

[161] S Gluck and F Gorouhi ldquoClinical and economic benefitsof aromatase inhibitor therapy in early-stage breast cancerrdquoAmerican Journal of Health-System Pharmacy vol 68 pp 1699ndash1706 2011

[162] R D Rao andM A Cobleigh ldquoAdjuvant endocrine therapy forbreast cancerrdquo Oncology vol 26 pp 541ndash547 2012

[163] S F Dent R GaspoM Kissner and K I Pritchard ldquoAromataseinhibitor therapy toxicities and management strategies in thetreatment of postmenopausal women with hormone-sensitiveearly breast cancerrdquo Breast Cancer Research and Treatment vol126 no 2 pp 295ndash310 2011

[164] J J Body ldquoIncreased fracture rate in women with breast cancera review of the hidden riskrdquo BMC Cancer vol 11 article 3842011

[165] T Petit P Dufour and I Tannock ldquoA critical evaluationof the role of aromatase inhibitors as adjuvant therapy forpostmenopausal women with breast cancerrdquo Endocrine-RelatedCancer vol 18 no 3 pp R79ndashR89 2011

[166] E Amir B Seruga S Niraula L Carlsson and A OcanaldquoToxicity of adjuvant endocrine therapy in postmenopausalbreast cancer patients a systematic review and meta-analysisrdquoJournal of the National Cancer Institute vol 103 pp 1299ndash13092011

[167] R E Coleman and E V McCloskey ldquoBisphosphonates inoncologyrdquo Bone vol 49 no 1 pp 71ndash76 2011

[168] P Hadji J J Body M S Aapro et al ldquoPractical guidance forthe management of aromatase inhibitor-associated bone lossrdquoAnnals of Oncology vol 19 no 8 pp 1407ndash1416 2008

[169] R Wong and P J Wiffen ldquoBisphosphonates for the relief ofpain secondary to bone metastasesrdquo Cochrane Database ofSystematic Reviews no 2 Article ID CD002068 2002

16 ISRN Oncology

[170] M Aapro P A Abrahamsson J J Body et al ldquoGuidance on theuse of bisphosphonates in solid tumours recommendations ofan international expert panelrdquoAnnals of Oncology vol 19 no 3pp 420ndash432 2008

[171] M Gnant and P Hadji ldquoPrevention of bone metastases andmanagement of bone health in early breast cancerrdquo BreastCancer Research vol 12 article 216 2010

[172] M C Winter I Holen and R E Coleman ldquoExploring theanti-tumour activity of bisphosphonates in early breast cancerrdquoCancer Treatment Reviews vol 34 no 5 pp 453ndash475 2008

[173] I Holen and R E Coleman ldquoBisphosphonates as treatment ofbonemetastasesrdquo Current Pharmaceutical Design vol 16 no 11pp 1262ndash1271 2010

[174] T Powles A Paterson E McCloskey et al ldquoReduction in bonerelapse and improved survival with oral clodronate for adjuvanttreatment of operable breast cancerrdquo Breast Cancer Researchvol 8 no 3 article R13 2006

[175] M Gnant B Mlineritsch W Schippinger et al ldquoEndocrinetherapy plus zoledronic acid in premenopausal breast cancerrdquoThe New England Journal of Medicine vol 360 no 7 pp 679ndash691 2009

[176] R T Chlebowski and N Col ldquoBisphosphonates and breastcancer incidence and recurrencerdquoBreastDisease vol 33 pp 93ndash101 2011

[177] F H Sarkar Y Li Z Wang and D Kong ldquoThe role ofnutraceuticals in the regulation ofWnt andHedgehog signalingin cancerrdquoCancer andMetastasis Reviews vol 29 no 3 pp 383ndash394 2010

[178] A Ahmad S Padhye and F H Sarkar ldquoRole of novel nutraceu-ticals Garcinol Plumbagin and Mangiferin in the preventionand therapy of humanmalignancies mechanisms of anticanceractivityrdquo inNutraceuticals and Cancer F H Sarkar Ed pp 179ndash199 Springer New York NY USA 2012

[179] A Ahmad W A Sakr and K M W Rahman ldquoMechanismsand therapeutic implications of cell death induction by indolecompoundsrdquo Cancers vol 3 pp 2955ndash2974 2011

[180] S F Asad S Singh A Ahmad and S M Hadi ldquoFlavonoidsantioxidants in diet and potential anticancer agentsrdquo MedicalScience Research vol 26 no 11 pp 723ndash728 1998

[181] A AhmadWA Sakr andKMW Rahman ldquoAnticancer prop-erties of indole compounds mechanism of apoptosis inductionand role in chemotherapyrdquo Current Drug Targets vol 11 no 6pp 652ndash666 2010

[182] J Y Dong and L Q Qin ldquoSoy isoflavones consumption andrisk of breast cancer incidence or recurrence a meta-analysisof prospective studiesrdquo Breast Cancer Research and Treatmentvol 125 no 2 pp 315ndash323 2011

[183] Y Li M S Wicha S J Schwartz and D Sun ldquoImplications ofcancer stem cell theory for cancer chemoprevention by naturaldietary compoundsrdquo Journal of Nutritional Biochemistry vol22 no 9 pp 799ndash806 2011

[184] J Kim X Zhang K M Rieger-Christ et al ldquoSuppression ofWnt signaling by the green tea compound (-)-epigallocatechin3-gallate (EGCG) in invasive breast cancer cells requirementof the transcriptional repressor HBP1rdquo Journal of BiologicalChemistry vol 281 no 16 pp 10865ndash10875 2006

[185] A Ahmad W A Sakr and K M Rahman ldquoNovel targets fordetection of cancer and their modulation by chemopreventivenatural compoundsrdquo Frontiers in Bioscience vol 4 pp 410ndash4252012

[186] A Ahmad S H Sarkar A Aboukameel et al ldquoAnticanceraction of garcinol in vitro and in vivo is in part mediatedthrough inhibition of STAT-3 signalingrdquoCarcinogenesis vol 33pp 2450ndash2456 2012

[187] B Bao A Ahmad Y Li et al ldquoTargeting CSCs within thetumor microenvironment for cancer therapy a potential roleof mesenchymal stem cellsrdquo Expert Opinion on TherapeuticTargets vol 16 pp 1041ndash1054 2012

[188] Y LiM YMaitah A Ahmad D Kong B Bao and FH SarkarldquoTargeting theHedgehog signaling pathway for cancer therapyrdquoExpert Opinion onTherapeutic Targets vol 16 pp 49ndash66 2012

[189] M F Ullah A Ahmad H Zubair et al ldquoSoy isoflavonegenistein induces cell death in breast cancer cells throughmobi-lization of endogenous copper ions and generation of reactiveoxygen speciesrdquoMolecular Nutrition and Food Research vol 55no 4 pp 553ndash559 2011

[190] AVyas PDandawate S PadhyeAAhmad andF Sarkar ldquoPer-spectives on new synthetic curcumin analogs and their poten-tial anticancer propertiesrdquo Current Pharmaceutical Design Inpress

[191] Y Li T G Vandenboom D Kong et al ldquoUp-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreaticcancer cellsrdquo Cancer Research vol 69 no 16 pp 6704ndash67122009

[192] B Bao S Ali D Kong et al ldquoAnti-tumor activity of a novelcompound-CDF is mediated by regulating miR-21 miR-200and pten in pancreatic cancerrdquo PLoS ONE vol 6 no 3 articlee17850 2011

[193] B Bao Y Li A Ahmad et al ldquoTargeting CSC-related miRNAsfor cancer therapy by natural agentsrdquo Current Drug Targets vol13 no 14 pp 1858ndash1868 2012

[194] A Ahmad S H Sarkar B Bitar et al ldquoGarcinol regulates EMTand Wnt signaling pathways in vitro and in vivo leading toanticancer activity against breast cancer cellsrdquoMolecular CancerTherapeutics vol 11 pp 2193ndash2201 2012

[195] Z Wang Y Li D Kong et al ldquoAcquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistantpancreatic cancer cells is linked with activation of the notchsignaling pathwayrdquo Cancer Research vol 69 no 6 pp 2400ndash2407 2009

[196] ZWang Y Li A Ahmad et al ldquoTargeting miRNAs involved incancer stem cell and EMT regulation an emerging concept inovercoming drug resistancerdquo Drug Resistance Updates vol 13no 4-5 pp 109ndash118 2010

[197] V Raviraj H Zhang H Y Chien L Cole EWThompson andL Soon ldquoDormant but migratory tumour cells in desmoplasticstroma of invasive ductal carcinomasrdquo Clinical and Experimen-tal Metastasis vol 29 pp 273ndash292 2012

2 ISRN Oncology

years after the first intervention (Figure 1)This phenomenonis ldquotumor recurrencerdquo and the subject of our discussion here

2 Breast Cancer Recurrence

Recurrence of breast cancer is a major clinical manifestationand represents the principal cause of breast cancer-relateddeaths [7] A number of researchers have tried to predictsome sort of pattern for breast cancer recurrence This hasincluded studies in various breast cancer subtypes whereinbreast cancers are characterized by the presence of receptorssuch as estrogen receptor (ER) progesterone receptor (PR)and HER2ErbB2 receptor (HER2) or by the absence ofall of them the triple negative breast cancers (TNBCs) Adifferential pattern of recurrence between different breastcancer subtypes has been suggested and it appears [8ndash10]that ER-negative breast cancers are associated with higherrisk of recurrence during the initial 5 years after diagnosiscompared to ER-positive breast cancers Thereafter the riskof recurrence chronically increases in ER-positive breastcancers for the next 10 years and at 15 years followingdiagnosis the risk appears to be equal for both subtypesIn ductal carcinoma in situ it has been analyzed that theER-negativePR-negative but HER2-positive cancers havehigher risk of recurrence compared to ER-positivePR-positiveHER2-negative cancers [11] The TNBCs markedby absence of ERPRHER2 are generally associated withhigh risk of recurrence with particularly high risk of distantrecurrences in brain and visceral metastases compared toreceptor positive tumors [12]

In addition to the simple classification of breast cancersdescribed previously there are other subclassifications ofbreast cancers as well such as the one that classifies breastcancers into luminal A luminal B basal and HER2 enriched[13] The luminal A subtype includes ER-positive andorPR-positive HER2-negative breast cancers luminal B sub-type includes ER-positive andor PR-positive HER2-positivebreast cancers basal subtype includes ER-negative PR-negative HER2-negative breast cancers which may also bepositive for EGFR and HER2-enriched subtype includes ER-negative PR-negative and HER2-overexpressing breast can-cers The existence of such subtypes which are at time over-lapping but most of the time so distinct presents a challengeto the choice of appropriate therapy This has led to the pro-posal of personalized therapy that fits the needs of individualpatients

Irrespective of the underlying breast cancer subtype alarge number of advanced stage breast cancers are markedby metastases to lymph nodes and overall the presenceof axillary lymph node metastases is associated with con-siderable poor disease-free as well as overall survival [14]Axillary lymph node metastases remain a very importantprognostic variable and identification of molecular markersfor development of lymph node metastases can potentiallyhelp intervene early reducing the chances of breast cancerrecurrence [15]

3 Cancer Recurrence in Breast CancerPatients Undergoing Surgery

Surgical intervention is one of the options for breast cancerpatients [16] The choice for surgical intervention largelydepends on the cancer stage For patients presenting withearly stage breast cancer the two most common treatmentoptions available are breast conserving surgery followed byradiation therapy ormastectomy [17ndash19]Mastectomyusuallydoes not need subsequent radiation therapy It seems thatthere are distinct risk factors of recurrence in breast can-cer patients undergoing mastectomy versus those choosingbreast conserving therapy [20]Whereas lymphnode involve-ment and tumor size are major risk factors after mastectomythe young age and presence of ductal carcinoma in situare major risk factors after breast conservation therapy Thedistinct clinical and histopathological determinants resultin differential response to radiotherapy and point to theneed for more robust personalized therapies and follow-up procedures for patients opting for different surgicalinterventions Further complicating the decision of surgeonsperforming breast conserving therapy is the realization thatsurgical margins also seem to impact the recurrence of breastcancer [21] In a study [17] that scanned published reportsand systematically reviewed the local recurrence in breastcancer patients undergoing mastectomy with or withoutbreast reconstruction it was concluded that the recurrencerates were not higher in patients that underwent breastreconstruction Also radiation therapy is generally associatedwith reduced recurrence in breast cancer and a recent meta-analysis [22] of 10801 patients from 17 randomized trials hasconcluded that radiotherapy reduces the recurrence rate byhalf and the death rate by about a sixth in patients that haveundergone breast conserving surgery Interestingly this studyalso identified many factors that might influence the extentof radiotherapy-induced benefits Such factors include agecancer grade estrogen receptor status and use of tamoxifenas well as the extent of surgery

In a study [23] that looked at the influence of molecularsubtypes of breast cancers namely ER-positive PR-positiveand HER2-overexpressing as well as TNBC in relation torecurrence in patients with mastectomy versus breast con-serving surgery a differential rate of recurrence was observedin patients with different molecular subtypes This studyanalyzed data from 15 different studies covering a total of12592 patients of which 57 underwent breast conservingtherapy while 43 underwent mastectomy It was observedthat among the patients that underwent breast conservingtherapy patients with ER-positive and PR-positive breastcancers had many reduced instances of recurrence thanHER2-overexpressing and TNBC patients Similar resultswere observed for mastectomy patients as well where ER-positive and PR-positive patients were again found to be at alesser risk of recurrence compared to HER2-overexpressingand TNBC patients Although both HER2-overexpressingand TNBC patients were found to be at a higher risk of recur-rence a direct comparison between the two subtypes revealedthat HER2-overexpressing breast cancer patients presentedhigher risk of recurrence in patients undergoing breast

ISRN Oncology 3





tumor


Time lapse









4 ISRN Oncology

Cancer stem cell



Induction of EMT

Modulated miRNAs

Quiescence

IncreasedDNA repair








ISRN Oncology 5










6 ISRN Oncology









ISRN Oncology 7









8 ISRN Oncology










ISRN Oncology 9










10 ISRN Oncology






CSCs

EMT


miRNAs




References




ISRN Oncology 11



































12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























ISRN Oncology 3





tumor


Time lapse









4 ISRN Oncology

Cancer stem cell



Induction of EMT

Modulated miRNAs

Quiescence

IncreasedDNA repair








ISRN Oncology 5










6 ISRN Oncology









ISRN Oncology 7









8 ISRN Oncology










ISRN Oncology 9










10 ISRN Oncology






CSCs

EMT


miRNAs




References




ISRN Oncology 11



































12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























4 ISRN Oncology

Cancer stem cell



Induction of EMT

Modulated miRNAs

Quiescence

IncreasedDNA repair








ISRN Oncology 5










6 ISRN Oncology









ISRN Oncology 7









8 ISRN Oncology










ISRN Oncology 9










10 ISRN Oncology






CSCs

EMT


miRNAs




References




ISRN Oncology 11



































12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























ISRN Oncology 5










6 ISRN Oncology









ISRN Oncology 7









8 ISRN Oncology










ISRN Oncology 9










10 ISRN Oncology






CSCs

EMT


miRNAs




References




ISRN Oncology 11



































12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























6 ISRN Oncology









ISRN Oncology 7









8 ISRN Oncology










ISRN Oncology 9










10 ISRN Oncology






CSCs

EMT


miRNAs




References




ISRN Oncology 11



































12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























ISRN Oncology 7









8 ISRN Oncology










ISRN Oncology 9










10 ISRN Oncology






CSCs

EMT


miRNAs




References




ISRN Oncology 11



































12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























8 ISRN Oncology










ISRN Oncology 9










10 ISRN Oncology






CSCs

EMT


miRNAs




References




ISRN Oncology 11



































12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























ISRN Oncology 9










10 ISRN Oncology






CSCs

EMT


miRNAs




References




ISRN Oncology 11



































12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























10 ISRN Oncology






CSCs

EMT


miRNAs




References




ISRN Oncology 11



































12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























ISRN Oncology 11



































12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























12 ISRN Oncology




































ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























ISRN Oncology 13


































14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























14 ISRN Oncology



































ISRN Oncology 15


































16 ISRN Oncology





























ISRN Oncology 15


































16 ISRN Oncology





























16 ISRN Oncology





























ReviewArticle Pathways to Breast Cancer Recurrence...ISRNOncology 3 Early intervention and treatment...

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