Breast Cancer and the Environment and NIEHS Research Programs Leslie Reinlib, PhD Program Director National Institute o

1. Breast Cancer and the Environment and NIEHS Research ProgramsLeslie Reinlib, PhDProgram DirectorNational Institute of EnvironmentalHealth Sciences

2. Breast Cancer: Some History Queen Atossa Persia 500 BCE Hendrickje Stoffels Holland 17th Century Bathsheba’s Breast by James Olson 2002 William Stewart Halstead 1852 - 1922 Bernard Fisher 1920 - B. Fisher, S. Anderson, J. Bryant,  et al., N Engl J Med, 2002, vol. 347, pp. 1233-1241

3. Some Good News US 5-Year Survival Rates 1975 Overall 75% 2006 Overall 89% Localized 98% SEER Cancer Statistics Review National Cancer Institute

4. The Puzzle of Breast Cancer Diet Hormones Breast Cancer Age Genetics Lifestyle Exposures

5. BreastCancer and Environment • Established Risk Factors only partially explain Breast Cancer Risk => 25% - 50% of US Cases Madigan et al JNCI 87: 1681-1685 (1995) Rockhill et al Am J Epi 147: 826-833 (1998) • Genetics only partially explain Breast Cancer Risk => approx 5 – 10% of Cases Lichtenstein etal NEJM 343: 78-85 (2000) Sakorafas Cancer Treat Rev 29: 79-89 (2003) • Environmental Effects could explain 75% of Breast Cancer Risk => Twin Studies Lichtenstein etal 2000

6. Established Risk Factors • Gender • Age • History of non-cancerous breast disease • Starting monthly periods before age 12 • Starting menopause (“change of life”) after age 55 • More than 5 years of postmenopausal estrogen + progesterone replacement therapy • Never having children or first live birth after age 30 • Use of alcohol, especially two or more drinks daily • Obesity, esp excessive weight gain after menopause • Physical inactivity American Cancer Society Fact Sheet 2002

7. Environmental Influences on Breast Cancer: Then… • Black Bile 400 BCE – 1730 • Celibacy – 1713 Ramazzini’s Nun Study • Curdled Milk • Lymphatic Blockage • Depression

8. And Now… ChemicalUS ExposureBC ConnectionPhysiologyOther DES pregnant women  risk & mortality  birth wt; early (estrogen 1940-1971; in DES mothers (30-40%) thelarche; disrupt.) cattle feed=>1979 & daughters (20%-2.5X) estrogen mimic; hormone recptr; etc Phytoestrogens beans, soy,  estrogen in chng estrogen flax, grains Chinese women production & brkdn Omega3 fish may  BC risk(?) Fats/FA may little info Fatty Acids  estrogen; on diet early puberty after BC DDT/DDE ended 1970 no direct evidence lactation? low levels breast milk HRT hot flashes recurrence 3x  estrogen (BC survivors) Source: Cornell Univ Program on Breast Cancer and Environmental Risk Factors in NY State

9. Critical Windows of Exposure • Length of Exposure • Severity of Exposure • Developmental period • Age • Pregnancy

10. Mammary Gland Development: A Lifelong Process Life Cycle of Breast Development Russo J & Russo IHJournal of Mammary Gland Biology and Neoplasia;3:49-61 (1998) Russo etal, Mammary Gland Architecture and Susceptibility of Human Breast to Cancer. Breast Journal; 7:278-291 (2001)

11. Breast Cancer and the Environment Research Centers Partnerships Basic Science Researchers Epidemiologists Community Advocates and Members

12. Breast Cancer and the Environment Research Centers • Major Outcome is Puberty • How environmental exposures influence age and progression of puberty will likely produce: • New insights into the mechanisms of breast cancer • Information for public health messages to young girls and women at high risk about the roles of specific environmental stressors

13. Breast Cancer and the Environment Research Centers Two parallel projects Environmental Effects on the Molecular Architecture and Function of the Mammary Gland Across the Lifespan Aims: Explore normal development & chemically - induced changes in the architecture of the mammary gland Environmental and Genetic Determinants of Puberty Aims: Determine key environmental risk factors, genetic susceptibility on breast development (thelarche) & menarche. Study will focus on approx 1500 girls of diverse racial groups from across the nation.

14. Breast Cancer and the Environment Research Centers Robert Bornschein, Ph.D. University of Cincinnati Puberty & Cancer Initiation: Environment, Diet, & Obesity Jose Russo, M.D. Fox Chase Cancer Center Centers for Environment and Mammary gland Development Sandra Z. Haslam, Ph.D. Michigan State University Breast Cancer and the Environment Research Center Robert A. Hiatt, M.D., Ph.D. University of California at San Francisco Bay Area Breast Cancer & the Environment Research Center

15. Breast Cancer and the Environment Research Centers

16. Breast Cancer and the Environment Research Centers Major Themes Biomarker discovery for tumor initiation Diet, age, environmental chemicals, and irradiation examined at critical Windows of Susceptibility Role in altering mammary gland architecture of estrogen-active chemicals during critical periods of development Importance during gestation and lactation of high fat diets, elevated progesterone, estrogen, carcinogens Implications for breast cancer risk of modifiable factors that influence female sexual maturation

17. Breast Cancer and the Environment Research Centers Exposures Dietary factors: PAH, alkyl amines (PhiP*), omega & gamma fatty acids, PUFA, phytoestrogens Carcinogens: benzo(a)pyrene*, DMBA*, lead, PCB, PBDE, ochratoxin Endocrine Disruptors: dioxin, ICZ*, phthalates Other: irradiation*, energy balance, activity * animal studies

18. Environmental Chemicals can act like Natural Hormones and Estrogens Estradiol Enterolactone Bis(2ethylhexyl) phthalate

19. Breast Cancer and the Environment Research Centers Cross Collaborations • Animal models • Common Diets • Times/periods of exposures • Bioassays • Data • Epidemiology Studies • Questionnaires • Bioassays: choice of chemicals and coordinated detn • Bio Samples: collection, storage, sharing • Training; e.g. determination of staging

20. Breast Cancer and the Environment Research Centers Community Input into Exposures to Track in Human/Laboratory Studies

21. Urine Biomarkers Suggest Wide-Spread Levels of Common Exposures Mary Wolff, Susan Teitelbaum, Gayle Windham, Susan Pinney, Julie Britton, Carol Chelimo, James Godbold, Frank Biro, Lawrence H. Kushi, Christine M. Pfeiffer, Antonia M. Calafat. Pilot Study of Urinary Biomarkers of Phytoestrogens, Phthalates, and Phenols in Girls. Env Health Persp 2007; 115: 116. • Pilot study (90 girls; age 6–8) NYC, Cincinnati, SF Bay Area • Assayed urine for 25 biomarkers including triclosan, enterolactone, phthalates • Most markers found in 94% of the girls • Nine markers in 100% of the girls: • isoflavones = > soy • di(2-ethylhexyl) phthalate => plastics softening agent • Phthalates varied with race and body mass index & season • First report in children for some of the chemicals • Highest levels of enterolactone, benzo-phenome, MEP (phthalate)

22. First Study in School-Aged Children shows high levels of several persistent chemicals that act like hormones Windham GC, Pinney SM, Sjodin A, Lum R, Jones RS, Needham LL, Biro FM, Hiatt RA and Kushi LH. (2010) Body burdens of brominated flame retardants and other persistent organo- halogenated compounds and their descriptors in US girls. Environ. Res 2010 • Urine and blood samples examined in 600 girls aged 6 – 8 from Cincinnati/KY and Northern California • PBDE Seven congeners found in greater than 60% of girls • levels in CA girls were higher; AA among the highest • levels higher than reported for the general population • PCB Ten PCBs were detected in more than 60% of girls, with five found in nearly all girls • lowest levels were in AA or obese, or not breastfed • Chlorinated Pesticides Three pesticides detected in more than 60% of the girls; DDE found in nearly all and at far higher levels than the other two pesticides

23. Perfluorooctanoic acid(PFOA) Promotes Steroid Hormone Production in Ovaries and Stimulates Mammary Gland Growth Factors Zhao, Y, Tan YS, Haslam S, Yang C. PFOA effects on steroid hormone and growth factor levels mediate stimulation of peripubertal mammary gland development in C57Bl/6 mice. Toxicology Sciences 2010. • PFOA widely used on non-stick surfaces, MW popcorn • Animal studies suggest low toxicity. But mammary gland development could be affected by these steroid-like chemicals • Mammary gland stimulation by PFOA observed in mice • PFOA up-regulated protein levels of several key growth factors: • epidermal growth factor receptor • estrogen receptor α • hepatocyte growth factor • cyclin D1 proliferating cell nuclear antigen

24. Radiation speeds up the aging of Breast Cells Mukhopadhyay R, Costes SV, Bazarov AV, Hines WC, Barcellos-Hoff MH, and Yaswen P. Promotion of Variant Human Mammary Epithelial Cell Outgrowth by Ionizing Radiation: an Agent-Based Model Supported by In Vitro Studies. Breast Cancer Res. 2010; 10: R11. • Breast epithelial cells extracted from normal breast; grown in the lab for 8 days; exposed to radiation & compared with control cells. • Four – six weeks after radiation, most cells stop dividing • But daughter cells form more and larger patches of quickly growing cells, likely due to more space between them • Radiation could be speeding aging of normal cells, that creates space in the microenvironment for new, cancerous variants to fill.

25. Relationships between Urinary Biomarkers of Phytoestrogens, Phthalates, and Phenols and Pubertal Stages in Girls MS Wolff, et al. Relationships between Urinary Biomarkers of Phytoestrogens, Phthalates, and Phenols and Pubertal Stages in Girls. Env Health Persp 2010 • Data on full cohort of ~1200 girls • High molecular weight (HMW) phthalate weakly associated with pubic hair development (early onset puberty) • Inverse associations (later onset puberty) of breast stage with daidzein (soy); and of pubic hair with triclosan (cosmetic) and LMW phthtalate • Weak hormonally active agents had small associations with pubertal development.

26. National Meeting Early Environmental Exposures • New York, New York - November 16 - 18, 2010 • Program Committee and Session Moderators include Breast Cancer survivors and Advocates • Educational pre-meeting for non-scientists, advocates • Talks with the Experts – Informal sessions • Mini-symposia featuring Center scientists and invited speakers

27. BCERC Website http://www.bcerc.org

28. Breast Cancer and the Environment Research Centers NIEHS Les Reinlib, PhD – BCERP Director & Program Administrator Elizabeth Maull, PhD – Program Administrator Caroline Dilworth, PhD – Program Administrator Gwen Collman, PhD – Director, Extramural Research and Training