Etiology of Breast Cancer: with special attention to environmental factors

By: Saad Almasoud , Lamya Alomair, Amir Shams

George Mason University Spring 2013

Breast anatomy I

1-ribs:2-pectoralis muscle3-chest wall4-coopers ligaments5-small ducts and acini6-major ducts7-nipple8-lobule

Breast Anatomy IIThe lymph node bearing area has been divided into three axillary regions:Level 1: Lymph nodes lateral and inferior to the pectoralis minor muscleLevel 2: Lymph nodes under the pectoralis minor muscleLevel 3: Lymph nodes under and deep to the pectoralis minor muscle

Vascular and nervous system:1-The lateral border of the Pectoralis Minor and Major muscle2-The Latissimus Dorsi Muscle3-The Axillary Vein4-The Long Thoracic Nerve which innervates the Serratus Anterior Muscle5-The Thoraco-Dorsal Nerve which innervates the Latissimus Dorsi Muscle6-The Intercostal Brachial Nerve which is a sensory nerve for the inferior aspect of the arm and the posterior aspect of the axilla7-The Lateral Pectoral Nerve which innervates portions of the pectoralis muscle

Breast Development:Pre and post pubertal development

CHANGES ASSOCIATED WITH PREGNANCY As the output of oestrogen and progesterone produced first by the corpus luteum and

later by the placenta rises during pregnancy, the intralobular ductal epithelium proliferates and the cells increase in size: the number and length of the ductal branches therefore increase. Alveoli develop at their termini and expand as their cells and lumina fill with newly synthesized and secreted milk. The myoepithelial cells, which are initially spindle-shaped, become highly branched stellate cells, especially around the alveoli. Adjacent myoepithelial cells intermesh to form a basket-like network around the alveoli and ducts, interposed between the basal lamina and the luminal cells. Their cytoplasm contains actin and myosin filaments and they are contractile. There is a concomitant reduction in adipose tissue in the stroma. The numbers of lymphocytes, including plasma cells, and eosinophils increase greatly. Blood flow through the breast increases.

Secretory activity in the alveolar cells rises progressively in the latter half of pregnancy. In late pregnancy, and for a few days after parturition, their product is different from later milk and is known as colostrum, which is low in lipid but rich in protein and immunoglobulins. Colostrum confers a measure of passive immunity to the neonatal alimentary tract; it also has laxative properties. Proliferation of the glandular breast parenchyma results in an overall increase in breast size through gestation.

CHANGES ASSOCIATED WITH LACTATION True milk secretion begins a few days after parturition as a result of a reduction in

circulating oestrogen and progesterone, a change which appears to stimulate production of prolactin by the anterior hypophysis.

Milk distends the alveoli so that the cells flatten as secretion increases . The alveolar cell cytoplasm accumulates membrane-bound granules of casein and other milk proteins, and these are released from the apical plasma membrane by membrane fusion (merocrine secretion; see Ch. 2). Lipid vacuoles are formed directly in the apical cytoplasm as small lipid droplets which fuse with each other to create large ‘milk vacuoles' up to 10 μm across, that frequently protrude from the cell surface. These are released as intact lipid droplets with a thin surround of apical plasma membrane and adjacent cytoplasm (apocrine secretion). On hormonal stimulation by oxytocin, myoepithelial cells contract to expel alveolar secretions into the ductal system in readiness for suckling.

After the onset of lactation there is a gradual reduction in the numbers of lymphocytes and eosinophils in the stroma, although plasma cells continue to synthesize IgA for secretion into the milk. Alveolar cells take up IgA synthesized by adjacent plasma cells by endocytosis at their basal surfaces and secrete it apically, as dimers complexed to epithelial secretory component.Engorged Vs. Non lactating

Breast abnormalities Part I: non-proliferative lesion

What is mastalgia (breast pain)? Mastalgia is breast pain and is generally classified as either

cyclical (associated with menstrual periods) or noncyclic. Noncyclic pain may come from the breast or may come from somewhere else, such as nearby muscles or joints, and may be felt in the breast. Pain can range from minor discomfort to severely incapacitating pain in some cases. Many women with mastalgia worry more about the consequences of cancer than about the pain itself.

What is mastitis?Mastitis is inflammation of the breast. It is most often caused by a breast infection that affects women who are breast-feeding, but it can happen in any woman. A break in the skin or an opening in the nipple can allow bacteria to enter the breast duct, where they can grow. The body's white blood cells release substances to fight the infection. This causes swelling and increased blood flow. The area may become painful, red, and warm to the touch. Other symptoms can include fever and a headache. Mastitis is treated with antibiotics. In some cases, a breast abscess (a collection of pus) may form. Abscesses are treated by draining the pus, either by surgery or by using a needle (often guided by ultrasound), and then giving antibiotics. Having mastitis does not raise a woman's risk of developing breast cancer. But an uncommon type of cancer known as inflammatory breast cancer has symptoms that are a lot like mastitis and can be mistaken for an infection. If you are diagnosed with mastitis but antibiotic treatment does not help, a biopsy of the skin may be needed to be sure it is not cancer. Inflammatory breast cancer can spread quickly, so do not put off going back to the doctor if you still have symptoms after antibiotic treatment.

What is chronic sub areolar abscess?

Chronic sub areolar abscess is a breast infection that occurs infrequently. Surgery may be needed to stop this repeating infection. 

Duct ectasia Duct ectasia is also known as mammary duct ectasia. It is a

common condition that tends to affect women in their 40s and 50s. It occurs when a breast duct widens and its walls thicken, which can cause it to become blocked and lead to fluid build-up.

Duct ectasia may cause a sticky green or black discharge, which is often thick. The nipple and nearby breast tissue may be tender and red. The nipple may be pulled inward. Sometimes scar tissue around the abnormal duct causes a hard lump that may be confused with cancer.

This condition sometimes improves without treatment, or with warm compresses and antibiotics. If the symptoms do not go away, the abnormal duct can be removed through an incision (cut) at the edge of the areola (the darker colored area around the nipple).

Duct ectasia does not increase breast cancer risk.

What is fat necrosis?Fat necrosis is a condition in which painless, round, firm lumps caused by damaged and disintegrating fatty tissues form in the breast tissue. Fat necrosis often occurs in women with very large breasts or in response to a bruise or blow to the breast. This condition may also be the result of a lumpectomy and radiation from a previous cancerous lump. In some cases, physicians/care providers will watch the lump through several menstrual cycles, and may perform a mammogram before deciding whether or not to remove it. These lumps are not malignant and there is no reason to believe that they increase a woman's risk of cancer.

What is a cyst?

A cyst is a fluid-filled sac that develops in the breast tissue. Such cysts typically occur in women between the ages of 35 and 50 and are most common in those approaching menopause. They often enlarge and become tender and painful just before the menstrual period and may seem to appear overnight. Cysts are rarely malignant and may be caused by a blockage of breast glands.

Cysts can feel either soft or hard. When close to the surface of the breast, cysts can feel like a large blister, smooth on the outside, but fluid-filled on the inside. However, when they are deeply imbedded in breast tissue, cysts will feel like hard lumps because they are covered with tissue.

Breast abnormalities Type II: proliferative lesion without atypia

What is a Fibroadenoma?

Fibroadenomas are solid, smooth, firm, benign lumps that are most commonly found in women in their 20s and 30s. They are the most common benign lumps that occur in women and can occur in women of any age. Increasingly, they are being seen in postmenopausal women who are taking hormone therapy.

The painless lump feels rubbery and moves around freely and very often is found by the woman herself. Fibroadenomas vary in size and can grow anywhere in the breast tissue.

What is Sclerosing Adenosis?

Sclerosing adenosis is a breast condition that involves excessive growth of tissues in the breast's lobules, often resulting in breast pain. While these changes in the breast tissue are microscopic, they may show up on mammograms as calcifications and can produce lumps. Usually a biopsy is necessary to distinguish this condition from cancer. In addition, because the condition can be mistaken for cancer, the lumps are usually removed through surgical biopsy.

What is intraductal papilloma?

An intraductal papilloma is a small, wart-like growth that projects into the breast ducts near the nipple. This causes a bloody or sticky discharge. In addition, any slight bump or bruise near the nipple can cause the papilloma to bleed. If the discharge becomes bothersome, the duct can be surgically removed, often without changing the appearance of the breast.

While single papillomas most often affect women nearing menopause, multiple intraductal papillomas -- which often occur in both breasts -- are more common in younger women. Multiple intraductal papillomas are more likely to be associated with a lump than with nipple discharge. Any papilloma associated with a lump is surgically removed.

Bloody discharge

Uncontrolled Cell growth What is –plasia?What is benign growth?What is malignant growth?What is tumor?What is cancer?

What is Anaplasia?

Reversion of cells to an immature or a less differentiated form, as occurs in most malignant tumors.

What is Hypoplasia?1. Incomplete or arrested

development of an organ or part.2. Atrophy due to destruction of

some of the elements of a tissue or organ.

What is Hyperplasia?abnormal increase in the number

of normal cells in normal arrangement in an organ or tissue, which increases its volume.

What is Dysplasia?1. abnormality of development.2. in pathology, alteration in size,

shape, and organization of adult cells.

What is metaplasia?the change in the type of adult

cells in a tissue to a form abnormal for that tissue

What is Desmoplasia?The formation and proliferation of

fibroblasts and fibrous connective tissue, especially in tumors.

Last but not least :Neoplasia

Neoplasm is an abnormal mass of tissue as a result of neoplasia.

‘neoplasm’ means new growth without qualifying the nature of that growth .

What is neoplasm?any new and abnormal growth, specifically one in which cell multiplication is uncontrolled and progressive. Neoplasms may be benign or malignant.A neoplasm can be benign, potentially malignant

(pre-cancer), or malignant (cancer).

Types of neoplasmBenign :do not transform into cancer

.Potentially malignant: They do not

invade and destroy but, given enough time, will transform into a cancer.

Malignant neoplasms are commonly called cancer. They invade and destroy the surrounding tissue, may form metastases and eventually kill the host.

What is tumor?In modern medicine, the term

tumor means a neoplasm that has formed a lump.

Metastasis

Breast abnormalitiesType III: Atypical proliferative lesion

Ductal Carcinoma In-Situ (DCIS)

DCIS is a type of early breast cancer confined to the inside of the ductal system.

Infiltrating(invasive) Ductal Carcinoma (IDC)

IDC is the most common type of breast cancer representing 78% of all malignancies. These lesions appear as stellate (star like) or well-circumscribed (rounded) areas on mammograms. The stellate lesions generally have a poorer prognosis.

Infiltrating Lobular Carcinoma (ILC)

Infiltrating lobular carcinoma is a type of breast cancer that usually appears as a subtle thickening in the upper-outer quadrant of the breast. This breast cancer type represents 5% of all diagnosis. Often positive for estrogen and progesterone receptors, these tumors respond well to hormone therapy.

Rare breast cancer What is Paget disease of the breast? Paget disease of the breast (also known as Paget disease of the nipple and

mammary Paget disease) is a rare type of cancer involving the skin of the nipple and, usually, the darker circle of skin around it, which is called the areola. Most people with Paget disease of the breast also have one or more tumors inside the same breast. These breast tumors are either ductal carcinoma in situ or invasive breast cancer

Inflammatory Breast Cancer (IBC)

Inflammatory breast cancer is a rare and very aggressive type of breast cancer that causes the lymph vessels in the skin of the breast to become blocked. This type of breast cancer is called "inflammatory" because the breast often looks swollen and red, or "inflamed". IBC accounts for 1% to 5% of all breast cancer cases in the United States.

End of breast abnormalities

Hormone effects on breast development1-growth hormone(LH-FSH)2-estrogen(E1-E2-E3)3-progestrone4-prolactin 5-oxytocin6-testostrone

Luetinizing hormone Luteinizing hormone (LH, also known as lutropin [1] and

sometimes lutrophin [2]) is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH ("LH surge") triggers ovulation[3] and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone (ICSH),[4] it stimulates Leydig cell production of testosterone.[3] It acts synergistically with FSH.

Follicle-stimulating hormone(FSH) Follicle-stimulating hormone (FSH) is a hormone found in

humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland.[1] FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) act synergistically in reproduction. Specifically, an increase in FSH secretion by the anterior pituitary causes ovulation.

Progesteron

Progesterone also known as P4 (pregn-4-ene-3,20-dione) is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.

prolactinProlactin (PRL) also known as

luteotropic hormone (LTH) is a protein that in humans is encoded by the PRL gene.[1]

Prolactin is a peptide hormone discovered by Henry Friesen. Although it is perhaps best known for its role in lactation, prolactin already existed in the oldest known vertebrates—fish—where its most important functions were probably related to control of water and salt balance.

Estradiol during menstrual cycle

LOOKING FOR CLUES :

Very briefly

Epidemiology of breast cancerStudying the factors that are

thought to increase the risk of breast cancer by Statistics

1-Gender A-From the available evidence, breast cancer is predominantly a disease, which develops

in women although in rare circumstances the condition can be diagnosed in males. B-It seems likely that estrogen has some role in the development of breast cancer, which

would explain why there is almost a 100 -fold difference in breast cancer incidence between males and females.

C-However the difference in incidence may be because in females estradiol is able to exert a direct biological effect on breast cells, whereas in males testosterone needs to be converted to estradiol before exerting any biologic effect

2-Age A-breast cancer is relatively rare in young women who are

younger than 40 years of age. Some 161 cases were diagnosed in women under the age of 40 years during 1996, and the incidence increases with increasing age .

3-Menarche-establishment of regularityA-The establishment of regular

menstrual cycles within one year of the first menstrual cycle has been found to double the risk of breast cancer, compared to a situation where menstrual cycles establish regularity in five or more years

rapid establishment of regularity in menstrual cycles increased the risk of developing breast cancer four-fold (Henderson et ah, 1981).

4-Menarche-LengthA-The length of the menstrual cycle

and the duration of menstrual activity have been positively correlated with breast cancer risk.

B-regular menstrual cycle of 28 days is not only associated with the regular cycling of estrogen and progesterone but also the cycle of cell multiplication (mitosis) and cell death (apoptosis).

5-Parity-Age at full term pregnancyThe same researchers also found that if a

woman gave birth to her first child under the age of eighteen, that she would only have 40 percent of the breast cancer risk of a nulliparous woman (MacMahon et al., 1970). This decrease in risk, (compared to the risk for a woman with a first full term birth after the age of thirty years), is widely supported throughout the literature, even though the strength of the association varies from one study to another (MacMahon et aI., 1970; Kelsey et al., 1993).

6-Parity-high number of birthA-high parity (or a high number of

births) provides additional protection against the risk of developing breast cancer, independent of the age at first birth.

B-If a woman's second birth occurred under the age of 25 years, the risk of developing breast cancer was only one third of that of a woman who had only one birth under the same age (MacMahon et al., 1982).

7-Parity-Incomplete pregnancyA-Some researchers have investigated the link

between incomplete pregnancies, arising from spontaneous or induced abortions, and breast cancer.

B-Their research is based on the assumption that the risk of breast cancer may be increased because the birth does not go to term, and would no longer have a protective effect (pike et al., 1981; Hadjimichael et al., 1986; Parazzini et al., 1991).

C-women who had at least one abortion before their first full term pregnancy, had approximately 20% greater risk of developing breast cancer, than women who did not have any incomplete pregnancies.

8-pregnancies not followed by breastfeeding A-The fact that these women did

not breastfeed when their breasts had developed for nursing, resulted in a greater likelihood of breast cancer development (Wainwright, 1931).

9-Early menstrual and late MenopauseA combination of early age at

menarche and a late age at menopause would therefore prolong the time o f the menstrual cycling o f sex hormones, and thus would substantially increase a woman's risk of breast cancer development (Henderson et al., 1985; Rosner et al., 1994).

10-Family History-KinshipA-Data from the Nurse's Health Study, which

began in 1976 and recruited biannually until 1990, suggested that the degree of kinship and the number of closely affected relatives forms a strong relationship with breast cancer development (Colditz et al., 1996).

B-there was a 2.3 fold higher risk (relative risk; 1.9 - 2.7, 95% confidence intervals) of developing breast cancer if the participant had a first degree relative affected, as compared to women with no family history of the disease.

Genetics cluesHER2RASPI3KAKTCyclin

D1C-mycC-fos4e-elf

• P53• P27• BRCA-1• BRCA-II• BRCA-III• CHK-2• ATM• PTEN

11-Oral ContraceptiveA-The very long use of oral

contraceptives by young women before first full term pregnancy may be a very important factor that puts them at great risk of breast cancer.

B-For a pill containing a combination of progesteron and greater than 50micro.g of estrogen, the relative risk of breast cancer is lower than if the combination pill contains less than 50microg of estrogen

12-hormone replacement therapyA-studies have suggested that

HRT use may increase the risk of some cancers, especially endometrial, ovarian, cervical, and breast cancers ( ARONSON-et.al)

13-Life style-weightA-In women there are three main lifetime

periods in which substantial weight gain occurs; during menarche fatty deposits accumulate in the hips and buttocks; and during pregnancy and menopause there is an increase in body fat distribution centrally and in the breasts .

B-Some researchers suspect that a greater weight gain during adolescence, accompanied by little physical activity, is related to a greater risk of breast cancer.

14-Life style-Alcohol ConsumptionA-Alcohol consumption is one of the

only established dietary factors that has been associated with breast cancer risk.

B-light alcohol intake was associated with a weak to modest correlation with breast cancer risk, whilst intakes of 24 grams per day or more, was associated with a significant increased risk.

End of Part two

What did we describe so far

Breast Anatomy

& Breast

Development

Breast Abnormali

ties&

Breast Cancer

Looking for clues

NEXT Step :

Cure and Prevention

How Bad is it?2009 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2009.

Men292,540

Women269,800

26% Lung & bronchus

15% Breast9% Colon & rectum

6% Pancreas 5% Ovary 4% Non-Hodgkin

lymphoma 3% Leukemia3% Uterine corpus

2% Liver & intrahepaticbile duct

2% Brain/ONS25% All other sites

Lung & bronchus 30%Prostate 9%Colon & rectum 9%Pancreas 6%Leukemia 4%Liver & intrahepatic 4%

bile ductEsophagus 4%Urinary bladder 3% Non-Hodgkin 3%

lymphoma Kidney & renal pelvis 3%All other sites 25%

Trends in the Number of Cancer Deaths Among Men and Women, US, 1930-2006

0

50,000

100,000

150,000

200,000

250,000

300,000

1930 1940 1950 1960 1970 1980 1990 2000

Women

Men

Num

ber o

f Can

cer D

eath

s

265,000

270,000

275,000

280,000

285,000

290,000

295,000

Men

Women

Source: US Mortality Data, 1930-2006, National Center for Health Statistics, Centers for Disease Control and Prevention, 2009.

Very complex diseaseNo one single factor

associated with causing the disease

Breast cancer develops over a long period of time, usually 10 to 30 years

The puzzle of breast cancer

Risks related to breast cancer

Risks related to breast cancer

Risks related to breast cancer

Therapy and Drug

Drugs which target Breast Cancerall drugs that have been approved by the U.S. Food and Drug Administration for use as a breast cancer treatment.

Chemotherapy: stop cancer cells from dividing and growing

1-Cyclophosphamide ex.Cytoxan2-Doxorubicin ex.Doxil3-Carboplatin ex.Paraplatin4-Paclitaxel ex.Taxol5-Vinorelbine ex. Navelbine6-Other Chemotherapy drugs Adrucil® / Fluorouracil (5-FU) Gemzar ®/ Gemcitabine Camptosor ® / Irinotecan Ixempra® / Ixabepilone Methotrexate Temodar® / Temozolomide Topotecan Vincristine Vinblastine Xeloda® / Capecitabine High dose chemotherapy with stem cell

rescue

Hormone Therapy: prevent positive cells from being exposed to the hormones that cause them to grow Evista® / Raloxifene Fareston® / Toremifine Faslodex® / Fulvestrant Nolvadex® / Tamoxifen Arimidex / Anastrozole Aromasin / Exemestane Femara / Letrozole Lupron® / Leuprolide Plenaxis® / Abarelix Suprefact® / Buserlin Zoladex® / Goserelin

Bisphosphonate Therapytreat breast cancer that has spread to the bone.Actonel® / RisedronateAredia® / PamidronateBoniva® / IbandronateFosamex® /AlendronateXgeva® /DenosumabZometa® / Zoledronate

Targeted Biological Therapyfocus on blocking the actions of certain normal body proteins that allow cancer cells to grow and divide.Herceptin® / TrastuzumabLapatinib® / TykerbAvastin® / Bevacizumab

Only Practical method

Prevention :One logical response to the

growing breast cancer burden is to develop effective prevention strategies [1-3]

Why Prevention is Virtually Impossible?What is hard to prevent:

Although many breast cancer risk factors have been identified that might form the basis of such strategies, prevention remains challenging, and virtually impossible due to practical difficulties in modifying risk-increasing factors like nulliparity, late age at first full-term pregnancy, early age at menarche, and late age at menopause [1,2].

One Example is Environmental Risk FactorsDo environmental chemicals

affect the risk of cancer?This is a question being asked by

scientists, cancer advocates, educators, policy makers, and those exposed to environmental chemicals in their homes and workplaces.[3-4]

One of the first publications

Studies in migrants have shown increases in breast cancer incidence and mortality following migration from a lower- to a higher-risk country.(12–14) For example, Japanese immigrants in Los Angeles County had a clearly higher rate of breast cancer than Japanese in Japan.(12) Furthermore, the incidence of breast cancer in first-generation Japanese immigrants in Sao Paulo from 1968 to 1978 was higher than that among Japanese living in Japan, whereas mortality increased from 1979 to 2001 to a rate intermediate between that of Japanese living in Japan and Brazilians living in the state of Sao Paulo.(13,14) These findings strongly suggest that breast cancer risk is influenced by factors associated with the lifestyle or environment of the destination country[2].

Do environmental chemicals affect the risk of cancer?

81

NCI will prioritize gene-environmental studies in 2002

Environment factors 1-Occupational ExposureIncluding nurses, teachers, beauticians, airline attendants, lab technicians, telephone and telegraph operators, electronic workers, agriculture workers, leather and fur processors, glass manufacturing workers, and metal fitters and assemblers (Aronson et al., 1999; Band et al., 2000; Gardner et al., 2002; Peplonska et al., 2007; Teitelbaum et al., 2003).

Environment factors 2- Ionizing RadiationHigh exposures to ionizing radiation related to medical diagnosis or treat- ment was associated with breast cancer (Doody et al., 2000; National Academy of Sciences, 2005). Women with benign breast disease or a family history of breast cancer may have increased breast cancer risk following relatively low-level exposure to ionizing radiation (Hill et al., 2002).

Environment factors 3-Environmental

Contaminants

Old Contaminant Story :DDT

Deep Impact

The Other :AtrazineMost widely used herbicide in the USFirst registered for use in 1959Annual crop land usage

◦ Up to 77.3 million lbs active ingredient*

*Source: Asplein, 1999

Other Environmental Contaminants1-Polychlorinated Biphenyls (PCBs) 2-p,p′-DDE and p,p′-DDT 3-Mirex 4-Hexachlorobenzene (HCB) 5-Dieldrin 6-Chlordane 7-TCDD8-Triazine herbicides 9-Cadmium (Cd) 10- Polycyclic aromatic hydrocarbons

(PAHs)

Systematic review of environmental risk factors of Breast Cancer

Case study Analysis

Statistical Analysis

Logistic Regression Analysis on NHANES Questionnaire

Some of our results• Analysis 1: Analysis of

environmental Risk Factors as predictor for Breast Cancer 2008

Some of our resultsAnalysis 2: Analysis of

environmental Risk Factors as predictor for Breast Cancer 2007

Some of our resultsAnalysis 3: Analysis of

environmental Risk Factors as predictor for Breast Cancer 2006

Thank you !Question?

Reference: News-medical. [http://www.news-medical.net/health/Breast-CancerEpidemiology.aspx]. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008:

GLOBOCAN 2008. Int J Cancer 127:2893–2917   Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008, Cancer Incidence and Mortality

Worldwide: IARC CancerBase No. 10. Lyon: International Agency for Research on Cancer, 2010. [Cited 14 Apr 2011.] Available from URL: http://globocan.iarc.fr/

The oncology channel. [http://www.oncologychannel.com/breastcancer/index.shtml]. Salehi, F., et al., Review of the etiology of breast cancer with special attention to organochlorines as potential

endocrine disruptors. J Toxicol Environ Health B Crit Rev, 2008. 11: p. 276 - 300.   Ferlay J, Parkin DM, Curado MP et al. Cancer Incidence in Five Continents,Volumes I–IX: IARC CancerBase No. 9. Lyon:

International Agency for Research on Cancer, 2010. [Cited 14 Apr 2011.] Available from URL: http://ci5.iarc.fr Ferlay J. World Health Organization, Mortality Database. [Cited 7 Jan 2010.]Available from URL:

http://www.who.int/whosis/whosis/ Hirabayashi Y, Zhang M. Comparison of time trends in breast cancer incidence (1973–2002) in Asia, from cancer

incidence in five continents, Vols IV–IX. Jpn J Clin Oncol 2009; 39: 411–12. Shin HR, Boniol M, Joubert C et al. Secular trends in breast cancer mortality in five East Asian populations: Hong Kong,

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based on data from 12 population-based cancer registries in the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol 2011; 41: 139- 47.

Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, Mack TM. Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles county. Br J Cancer 1991; 63: 963–6.

Tsugane S, de Souza JM, Costa ML Jr et al. Cancer incidence rates among Japanese immigrants in the city of Sao Paulo, Brazil, 1969–78. Cancer Causes Control 1990; 1: 189–93.

Iwasaki M, Mameri CP, Hamada GS, Tsugane S. Secular trends in cancer mortality among Japanese immigrants in the state of Sao Paulo, Brazil, 1979–2001. Eur J Cancer Prev 2008; 17: 1–8.