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

Cancer Statistics

• Cancer affects 1 in 3 people

• Worldwide incidence of 10M cases/year

• 555,500 Americans died from cancer in 2002

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

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%

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

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.

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

Age-Adjusted Female Cancer Death RatesAge-Adjusted Female Cancer Death Rates

EBCTG. Lancet. 2005 May 14-20;365(9472):1687-717.

33%

28%

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.

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

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?

Targets in Cancer

• Proliferation

• Apoptosis/survival

• Differentiation

Numerous Oncogenes Control Cell Growth

Growth factors (I)

Growth factor receptors (II) Intracellular

Transducers (III)

Intracellular receptors (II)

Transcription factors (IV)

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

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

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

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

• 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

New Targeted Biologic Therapies

Baselga and Norton. Focus on Breast Cancer. Cancer Cell; 1; 319-322

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

Estrogen and Estrogen Receptor as a Therapy for Breast Cancer

Benefit of Adjuvant TamoxifenBenefit of Adjuvant Tamoxifen

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

cyclins, GFs

Hanahan and Weinberg: The hallmarks of cancer. Cell. 2000

ER

Rb, PP2A

MMPs, Cadherins

telomerase

VEGF, Ets-1

ER

IGFs, Bcl2

ER

Estradiol

EREAP-1SP-1

D1/CDKsSTATs

ECM

Growth factors

Kinases

Co-regulatorsRNA

Estrogen Receptor as a ‘Signaling Node’

Loss of regulation of the cell cycle

DSB DNA repair complex

APOPTOSIS

DIFFERENTIATION

Parallels Between Normal and “Cancer” Stem Cells

Pardall et al. Nat Rev Cancer 3:895, 2003

Glinsky et al JCI, 115, 1507, 2005

A Model For “Cancer Stem Cells” In Treatment Resistance and Disease

Recurrence

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

“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

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

Breast Cancer Progression

Abba et al. Breast Cancer Res 2004 6:R499

Angiogenesis Inhibitors