REPRODUCTIVE PATHOPHYS III Cancers of the Reproductive System Julie Kasperzyk, Sc.D. November 12, 2012

Acquired capabilities of cancer From: Hanahan D. Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:

Additional characteristics of some cancers From: Hanahan D. Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:

Tumor development occurs in stages (1) Weinberg RA. How cancer arises. Sci Am Sep;275(3):62-70.

Tumor development occurs in stages (2) Weinberg RA. How cancer arises. Sci Am Sep;275(3):62-70.

Malignant versus Benign Tumors Malignant (cancer) cells invade neighboring tissues, enter blood vessels, and metastasize to different sites Time Benign (not cancer) tumor cells grow only locally and cannot spread by invasion or metastasis

DNA Mutation Additions Deletions Normal gene Single base change DNA C T AGCGAACTAC AGGCGCTAACACT AGCTAACTAC AGAACTAC

General genetic abnormalities in cancer cells (1) A.Oncogenes get activated or become expressed more than normal –Oncogene: a gene that, when mutated or dysregulated, participates in the onset and development of cancer –The protein may be expressed at a greater level (more protein in the cell) become more active lose its potential to be regulated increase its stability (hang around in the cell longer) –These changes can cause the cell to be hyper-responsive to growth signals, grow in the absence of proper growth signals, evade apoptosis, etc.

A) Oncogene example: HER2+ breast cancer

B.Tumor suppressor genes stop working –Tumor suppressor gene: a gene that protects a cell from one step in the cancer pathogenesis process –The gene product may be a protein that maintains the normal cell cycle, inhibits an oncogene, inhibits cell division, etc. –When a tumor suppressor gene is mutated or dysregulated, the cell can progress to cancer if other aberrations are also present General genetic abnormalities in cancer cells (2)

Normal cellCell suicide (Apoptosis) p53 protein Excessive DNA damage B) Tumor suppressor example: p53 loss In normal cells, p53 protein triggers apoptosis

A.Viruses –DNA (ex: HPV) –RNA retroviruses (ex: HIV) B.Chemical carcinogens –Can cause chemical changes in DNA, DNA breaks, and/or inflammation –Ex: asbestos, benzene, diesel exhaust C.UV and ionizing radiation –Causes chromosomal breaks and translocations, and can interfere with DNA repair Environmental carcinogens

Cancer can spread to other sites (1) Ruoslahti E. How cancer spreads. Sci Am Sep;275(3):72-7.

Cancer can spread to other sites (2) Ruoslahti E. How cancer spreads. Sci Am Sep;275(3):72-7.

New cases of cancer in the US American Cancer Society. Cancer Facts & Figures Atlanta: American Cancer Society.

Cancer deaths among US men

Cancer deaths among US women (includes cervix)

MALE CANCERS

Testicular cancer Very rare: 8,590 new cases and 360 deaths annually in US Most common form of cancer in men Median age at diagnosis is 33 Most (90%) of cases arise from germ cells in the testes

Testicular cancer risk factors a)Northern European residence b)Family history c)Race/ethnicity: rates are 6x higher in Caucasians than African americans d)Testicular dysgenesis syndrome e)Carcinoma in situ can sometimes progress to invasive cancer f)HIV infection (debatable) g)Body size: taller and leaner men show highest risk

Height (per 5cm) & testicular cancer risk British Journal of Cancer (2010) 103, 1467 – 1474

BMI (per kg/m 2 ) & testicular cancer risk British Journal of Cancer (2010) 103, 1467 – 1474

Family history & prostate cancer risk Bratt et al. J Urol 2002;168:906-13

Genetics & prostate cancer: 8q24 Multiple genetic variants in this region found to increase PCa risk in variety of racial/ethnic groups Not in a coding region Closest gene is MYC, a transcription factor and oncogene Not clear how/if risk variants in 8q24 regulate MYC function or expression Amundadottir et al. Nat Genet Jun;38(6): Freedman et al. Proc Natl Acad Sci U S A Sep 19;103(38):

8q24 “Gene Desert” Region and Associations with Various Cancers 26 J Natl Cancer Inst 2008;100: 962 – 966 PROSTATE COLORECTAL OVARIAN BREAST PROSTATE

Prostate cancer incidence & mortality rates by race World J Urol (2012) 30:195–200

Diet & prostate cancer risk Dietary factorDirection of effect Calcium  (fatal & adv disease) Processed meat intake ()() Fish intake  (fatal disease) Vitamin D ()() Tomatoes/tomato based products “Mediterranean diet” Coffee   (adv disease) Giovannucci et al. Int. J. Cancer: 121, 1571–1578 (2007) Wilson et al. J Natl Cancer Inst. 2011;103(11): Chan et al. J Clin Oncol 23:

Other risk factors for prostate cancer Risk factorDirection of effect Accumulating evidence Growth Factors (IGF-I)  Genetic factors  or  Height  (fatal disease) BMI  (adv/fatal disease) Possible factors Physical activity - vigorous  (fatal disease) Long-term smoking Inflammation/Infections  (fatal disease) 

Height & BMI: potential mechanisms Height –Proxy for nutritional status in early life –Growth factors and hormones Obesity –Increased total energy intake –Metabolic syndrome & poor insulin control  increased cell proliferation

Role of energy balance in cancer development Exp Diabetes Res. 2012;2012:789174

Infection & prostate cancer: T. vaginalis Parasitic protozoan Infection affects 5-20% of U.S. young adults, typically asymptomatic in males Causes inflammation and may induce anti-apoptosis genes Preliminary data suggest that infection is linked to higher risk of aggressive prostate cancer

FEMALE CANCERS

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American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011.

Breast cancer risk factors: high estrogen exposure Reproductive factors that increase level or duration of exposure to estrogen increase risk –Nulliparity –Early menarche –Late menopause –Postmenopausal hormone use –Older forms of birth control pills (high estrogen) –Postmenopausal obesity (fat cells produce estrogen) –Alcohol use (increases conversion of testosterone to estrogen)

Breast Disease 24 (2005,2006) 17–35 Risk factors for postmenopausal breast cancer across the life course

Race/Ethnicity and Breast Cancer American Cancer Society. Breast Cancer Facts & Figures Atlanta: American Cancer Society.

Heredity and Breast Cancer Inherited factor(s) All Breast Cancer Patients Other factor(s)

BRCA1 & BRCA2 mutations Tumor suppressor genes Normally, BRCA1 and BRCA2 help to stabilize DNA and prevent uncontrolled cellular proliferation Prevalence of BRCA1 mutations in the general population is estimated between 1/500 to 1/1000 Prevalence of BRCA2 mutations is lower, but not known precisely

BRCA mechanism Hum Mol Genet. 2001;10:705-13

43 Am.J. Hum. Genet. 52: , 1993 BRCA1 & breast-ovarian cancer risk

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American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011.

Cervical cancer risk factors Virtually all cervical cancers are caused by HPV infections Other risk factors: –Sexual behavior: 1 st intercourse at early age; multiple partners –Family history –Poor diet and overweight –HIV infection (weakens immune system) –Oral contraceptives –Multiple pregnancies May reflect sexual behaviors

HPV infection DNA virus Viral proteins (E6 & E7) disrupt tumor suppressor genes in infected cells 100+ subtypes, but only some (mainly HPV-16 and HPV-18) can cause cervical cancer Most infections cleared by the immune system without any clinical symptoms Gynecologic Oncology Volume 107, Issue 2, Supplement 2007 S2 - S5

Prevalence of HPV-16 in serum Infect Dis Obstet Gynecol. 2006;2006 Suppl:40470.

Cumulative incidence of CIN after HPV infection Infect Dis Obstet Gynecol. 2006;2006 Suppl: Cervical Intraepithelial Neoplasia (CIN): precancerous lesion

Endometrial cancer Most common gynecological cancer in the US

Endometrial cancer risk factors Reproductive factors that increase exposure to estrogen increase risk (similar to breast cancer) –Nulliparity, early menarche, late menopause –Postmenopausal hormone use with estrogen and not progesterone (progesterone lowers risk by reducing growth of the endometrium) –Older forms of birth control pills with high estrogen –Obesity –Alcohol use –Prior breast cancer treatment with tamoxifen (acts as estrogen receptor antagonist in breast, but agonist in ovary) –Polycystic ovarian syndrome (PCOS)

Ovarian cancer Rare, occurs mainly in older women Rapidly fatal because difficult to detect in early stages ancer-statistics/ovarian- cancer/ovarian-cancer-survival-by- stage-at-diagnosis/

Ovarian cancer risk factors Prolonged exposure to high FSH & LH –Nulliparity –Oral contraceptive use decreases risk (reduced # of ovulations and lower FSH/LH) –Depletion of oocytes with age (less inhibin and estrogen reduces negative feedback on FSH & LH) –Fertility drugs (stimulate FSH & LH release) BRCA1 & BRCA2 mutations Obesity Androgen use

BURDEN OF OBESITY IN THE UNITED STATES

Obesity Trends* Among U.S. Adults BRFSS, 1985 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

Obesity Trends* Among U.S. Adults BRFSS, 1990 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

Obesity Trends* Among U.S. Adults BRFSS, 1995 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. Adults BRFSS, 2000 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends* Among U.S. Adults BRFSS, 2005 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Obesity Trends* Among U.S. Adults BRFSS, 2010 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Major obstacles to obesity control Genetic programming to store energy Abundance of energy-dense foods Poor adherence to calorie restriction Poor sleep Sedentary lifestyle Inadequate built environment to promote physical activity Cost of exercise programs/equipment No effective drugs to combat obesity High cost and risks of bariatric surgery Cancer Prev Res; 5(11); 1260–72.