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Adrian V. Lee, Ph.D.Adrian V. Lee, Ph.D.
Associate ProfessorAssociate Professor
Breast CenterBreast Center
Departments of Medicine and Departments of Medicine and Molecular and Cellular BiologyMolecular and Cellular Biology
Cancer Biology IICancer Biology IIComputer-Aided Discovery MethodsComputer-Aided Discovery Methods
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Cancer Statistics
• Cancer affects 1 in 3 people
• Worldwide incidence of 10M cases/year
• 555,500 Americans died from cancer in 2002
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US Mortality, 2004US Mortality, 2004
Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.
1. Heart Diseases 652,486 27.2
2. Cancer 553,888 23.1
3. Cerebrovascular diseases 150,074 6.3
4. Chronic lower respiratory diseases 121,987 5.1
5. Accidents (Unintentional injuries) 112,012 4.7
6. Diabetes mellitus 73,138 3.1
7. Alzheimer disease 65,965 2.8
8. Influenza & pneumonia 59,664 2.5
9. Nephritis 42,480 1.8
10. Septicemia 33,373 1.4
Rank Cause of DeathNo. of deaths
% of all deaths
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2007 Estimated US Cancer Deaths*
ONS=Other nervous system.Source: American Cancer Society, 2007.
Men289,550
Women270,100
26% Lung & bronchus
15% Breast
10% Colon & rectum
6% Pancreas
6% Ovary
4% Leukemia
3% Non-Hodgkin lymphoma
3% Uterine corpus
2% Brain/ONS
2% Liver & intrahepaticbile duct
23% All other sites
Lung & bronchus 31%
Prostate 9%
Colon & rectum 9%
Pancreas 6%
Leukemia 4%
Liver & intrahepatic 4%bile duct
Esophagus 4%
Urinary bladder 3%
Non-Hodgkin 3% lymphoma
Kidney 3%
All other sites 24%
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Change in the US Death Rates* by Cause, Change in the US Death Rates* by Cause, 1950 & 20041950 & 2004
* Age-adjusted to 2000 US standard population.Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.2004 Mortality Data: US Mortality Public Use Data Tape, 2004, NCHS, Centers for Disease Control and Prevention, 2006
HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
1950
2004
Rate Per 100,000
19.8
180.7
48.1
586.8
193.9
50.0
185.8217.0
0
100
200
300
400
500
600
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Trends in the Number of Cancer Deaths Trends in the Number of Cancer Deaths Among Men and Women, US, 1930-2004Among Men and Women, US, 1930-2004
0
50,000
100,000
150,000
200,000
250,000
300,000
1930 1940 1950 1960 1970 1980 1990 2000
Women
Men
Nu
mb
er o
f C
ance
r D
eath
s
265,000
270,000
275,000
280,000
285,000
290,000
2000 2001 2002 2003 2004
Men
Women
Source: US Mortality Public Use Data Tape, 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.
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Cancer Death Rates*, All Sites Combined, Cancer Death Rates*, All Sites Combined, All Races, US, 1975-2003All Races, US, 1975-2003
*Age-adjusted to the 2000 US standard population.Source: Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Mortality - All COD, Public-Use With State, Total U.S. (1969-2003), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2006. Underlying mortality data provided by NCHS (www.cdc.gov/nchs).
Men
Both Sexes
Rate Per 100,000
Women
0
50
100
150
200
250
300
1975 1978 1981 1984 1987 1990 1993 1996 1999 2002
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Age-Adjusted Female Cancer Death RatesAge-Adjusted Female Cancer Death Rates
EBCTG. Lancet. 2005 May 14-20;365(9472):1687-717.
33%
28%
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Decline in Breast Cancer Incidence Rates in 2003Decline in Breast Cancer Incidence Rates in 2003
Ravdin PM, N Engl J Med. 2007 Apr 19;356(16):1670-4.
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Why are we interested in the molecular biology of cancer?
• Cancer is a genetic disease– Agents that cause cancer cause genetic
change– Agents that cause genetic change cause
cancer
e.g. chemical carcinogens, ionizing radiation, viruses
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If we can understand the molecular biology of cancer we may be able to
– Prevent cancer– Better treat cancer
Why are we interested in the molecular biology of cancer?
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Targets in Cancer
• Proliferation
• Apoptosis/survival
• Differentiation
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Numerous Oncogenes Control Cell Growth
Growth factors (I)
Growth factor receptors (II) Intracellular
Transducers (III)
Intracellular receptors (II)
Transcription factors (IV)
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Selected Oncogenes and the Proteins of Their Proto-Oncogenes
OncogeneAnimal Retrovirus
Nonviral Tumor
Subcellular Location of Protein
Protein Encoded by Proto-Oncogene
Class I: Growth Factors
Sis Simian sarcoma Secreted Platelet-derived growth factor
Class II: Receptors
A. Cell-surface receptors with protein-tyrosine kinase activity
fms McDonough feline sarcoma
Plasma membrane
CSF-1 receptor
erbB Avian erythroblastosis Plasma membrane
Epidermal growth factor receptor
Neu (or erb-2)
Breast Cancer Plasma membrane
Related to epidermal growth factor receptorros UR II avian sarcoma
B. Intracellular receptorserbA Avian erythroblastosis Nuclear Thyroid hormone
receptor
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OncogeneNonviral Tumor
Subcellular Location of Protein
Animal Retrovirus
Protein Encoded by Proto-Oncogene
Class III: Intracellular Transducers
A: Protein-tyrosine kinase
src Rous avian sarcoma
Cytoplasm
yes Yamaguchi avian sarcoma
Cytoplasm
Fps (fes) Fujinami avian sarcoma (and feline sarcoma)
Cytoplasm Protein kinases that phosphorylate tyrosine residues
abl Abelson murine leukemia
Chronic myelogenous leukemia
Cytoplasm and nucleus
met Murine osteosarcoma
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OncogeneNonviral Tumor
Subcellular Location of Protein
Animal Retrovirus
Protein Encoded by Proto-Oncogene
C. Ras proteins
Ha-ras Harvey murine sarcoma
Bladder, mammary, and skin carcinomas
Plasma membrane
Ki-ras Kirsten murine sarcoma
Plasma membrane
Lung and colon carcinomas
N-ras
Neuroblastoma and leukemias
Plasma membrane
Guanine nucleotide-binding proteins with GTPase activity
D. Adaptorscrk Avian sarcoma
virusCytoplasm Contains protein with
SH2 and SH3 domains but not catalytic domain
B. Protein-serine/threonine kinasesmos Moloney murine sarcoma Cytoplasm
Protein kinases specific for serine or threonine
Raf (mil)
3611 murine sarcoma
Cytoplasm
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Class IV: Nuclear Transcription Factors
OncogeneNonviral Tumor
Subcellular Location of Protein
Protein Encoded by Proto-Oncogene
Animal Retrovirus
jun Avian sacroma virus 17
Nucleus
fos FBJ osteo-sarcoma
Nucleus
Transcription factor AP1
myc Avian MC29 Myelocytomatosis
NeuroblastoamaN-myc Nucleus
myb Avian myelo-blastosis
Leukemia Nucleus
ski Avian SKV770 Nucleus
rel Avian reticuloendotheliosis
Nucleus and cytoplasm
Protein that regulate transcription
Nucleus
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• 20-30% of primary invasive cancers overexpress HER-2 (90% of these are via gene amplification)
• Overexpression of HER-2 correlates with high mitotic rate and poor prognosis (node-positive patients)
• HER-2 overexpression is associated with a better patient resposne to doxorubicin, but a poor response to other drugs (methotrexate, 5-fluorouracil, cyclophosphamide and tamoxifen)
• Auto-antibodies to HER-2 are found in patient serum and may be a marker for tumor burden
• HER-2 is a therapeutic target using a humanized antibody (trastuzumab – Herceptin)
Targeted Biologic Therapies – HER2
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New Targeted Biologic Therapies
Baselga and Norton. Focus on Breast Cancer. Cancer Cell; 1; 319-322
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Bange et al. Molecular targets for breast cancer therapy and prevention. Nat Med 2001;7:548
Signaling is more complex than you can possibly imagine
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Estrogen and Estrogen Receptor as a Therapy for Breast Cancer
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Benefit of Adjuvant TamoxifenBenefit of Adjuvant Tamoxifen
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Stanford/Norway
Van’t Veer et al.
West et al.
Clustering of breast tumors associated with ER and coregulated genes
data from Sorlie et al. PNAS, 100: 8418, 2003
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cyclins, GFs
Hanahan and Weinberg: The hallmarks of cancer. Cell. 2000
ER
Rb, PP2A
MMPs, Cadherins
telomerase
VEGF, Ets-1
ER
IGFs, Bcl2
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ER
Estradiol
EREAP-1SP-1
D1/CDKsSTATs
ECM
Growth factors
Kinases
Co-regulatorsRNA
Estrogen Receptor as a ‘Signaling Node’
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Loss of regulation of the cell cycle
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DSB DNA repair complex
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APOPTOSIS
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DIFFERENTIATION
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Parallels Between Normal and “Cancer” Stem Cells
Pardall et al. Nat Rev Cancer 3:895, 2003
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Glinsky et al JCI, 115, 1507, 2005
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A Model For “Cancer Stem Cells” In Treatment Resistance and Disease
Recurrence
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Stem Cell
Self-renewal
Wntfamily
Notchfamily
Hedgehogfamily TGFβ
family
EGFfamily
FGFfamily
GH/IGF
Progesterone
Estrogen
Prolactin
Mammary Stem Cell Regulation
Modified from Clarke et al 2005
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“Within the next year, we will see medical centers targeting stem cells in almost every cancer,” said Dr. Max S. Wicha, director of the University of Michigan Comprehensive Cancer Center, one of the sites for the preliminary study that begins in the next few months (the other participating institutions are Baylor College of Medicine in Houston and the Dana-Farber Cancer Institute in Boston).
Scientists Weigh Stem Cells’ Role as Cancer Cause
By GINA KOLATAPublished: December 21, 2007
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Hedgehog Network Antagonists
Cyclopamine (CYC) • Plant derived – Corn lily • Causes birth defects• Binds and inactivates SMO
CUR0199691 (Curis Inc.)• One of three chemical
classes that inhibit SMO• Binds and inactivates SMO
Tomatidine (TOM)• Structurally similar to CYC• Does not inhibit Hedgehog
Cyclopia
VeratrumCalifornicum
C27H41NO2
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Breast Cancer Progression
Abba et al. Breast Cancer Res 2004 6:R499
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Angiogenesis Inhibitors