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Breast Cancer –

Breast Cancer –. Is there a link to Endocrine Disrupting Chemicals? Suzanne M. Snedeker, Ph.D. Assoc. Director for Translational Research Cornell University’s Program on Breast Cancer and Environmental Risk Factors (BCERF) sms31@cornell.edu http://www.cfe.cornell.edu/bcerf/.

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Breast Cancer –

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  1. Breast Cancer – Is there a link to Endocrine Disrupting Chemicals? Suzanne M. Snedeker, Ph.D. Assoc. Director for Translational Research Cornell University’s Program on Breast Cancer and Environmental Risk Factors (BCERF) sms31@cornell.edu http://www.cfe.cornell.edu/bcerf/

  2. Contribution of established factors to breast cancer risk • National surveys of US white women • 40-50% of breast cancer risk • Age first birth / nulliparity • Family history of breast cancer • Higher income Ref: Madigan et al., J Natl Cancer Inst, 87:1681-5, 1987 • North Carolina Breast Cancer Study • 25% of breast cancer risk • Menarche before 14 yrs • First birth at or after 20 yrs / nulliparity • Family history of breast cancer • History of benign breast disease Ref: Rockhill et al., Am J Epidemiology, 147:826-33, 1998

  3. Environmental links to breast cancer • Scandinavian Twin Study • 27% of risk, Heritable factors • 73% of risk, Environmental factors • 6% of risk, shared environment • 67% of risk, non-shared environment • Suggests that environmental factors play a major role in the causation of breast cancer Ref: Lichtenstein et al., New England J. of Medicine, 343:78-85, 2000

  4. Ionizing Radiation Risks Related to Breast Cancer Close Relative Genetics Advancing Age Gender Age at First Birth Passive Smoke Early Menarche Late Menopause Breast Feeding Education & Income Overweight (post-menopause) Chemicals -Work -Home -Garden -Recreation Lack of Exercise Diet Alcohol Hormone Therapy Benign Breast Disease ???

  5. Endocrine disrupting chemicals –Definitions • Endocrine Disruptor • Exogenous substance or mixture that alters the function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations • Potential Endocrine Disruptor • Exogenous substance or mixture that possess properties that might be expected to lead to endocrine disruption in an intact organism, or its progeny, or (sub)populations Ref: WHO/IPCS, Damstra et al. (eds), Global Assessment of the State-of-the Science of Endocrine Disruptors, 2002

  6. Endocrine disrupting chemicals –Possible modes of action Breast cancer risk

  7. Endocrine disrupting chemicals • Pharmaceuticals • Pesticides • Industrial Chemicals / Contaminants • Heavy Metals

  8. Endocrine disrupting chemicals–Ovarian hormones • Estrogen and progesterone have established roles in: • Normal mammary gland development in humans and rodent animal models • Regulation of breast cell proliferation during menstrual and estrous cycles • Humans – breast cell proliferation is the highest in luteal phase when progesterone levels highest; progestins do not “oppose” the action of estrogen in the breast Ref: Haslam et al., J Mammary Gland Biol Neoplasia, 7:93-105, 2002

  9. Endocrine disrupting chemicals–Ovarian hormones • In utero exposure to estrogen associated with higher breast cancer risk • Higher birth weight Ref: Michels, et al., Lancet, 348:1542-46, 1996 Kaijser et al., Epidemiology, 11:315-9, 2000 • Like-sexed female (dizygotic) twins Ref: Ekbom et al., J Natl Cancer Inst 88:71-6, 1997 Cerhan et al., J Natl Cancer Inst, 92:262-5, 2000 Hubinette et al., Int J Cancer 91:248-51, 2001 • Preeclampsia (lower estrogen, lower risk) Ref:Ekbom et al., Lancet, 340:1015-18, 1992 Ekbom et al., J Natl Cancer Inst 88:71-6, 1997

  10. Endocrine disrupting chemicals–Diethylstibesterol (DES) • DES–History of use in women • Pregnant women treated with DES to prevent miscarriages from 1940s to 1971 in US and 1978 in Europe; use continued in unindustrialized countries • Dosage typically 12,000 mg over 4 to 6 months • DES–History of use in livestock in US • Use as growth promoter in feed approved in 1954 • Ear implants approved in 1955 • Use in premixes revoked in 1972 because of detection of residues in edible tissues after slaughter • Use in livestock revoked by US Food and Drug Administration in 1978 / 1979 Ref: Calle et al., Am J Epidemiology, 144:645-52, 1996 DHEW, US FDA Judge Davidson brief, 1978 Huckell et al., Lancet, 348:331-1996

  11. Endocrine disrupting chemicals–Diethylstilbestrol (DES) • Human breast cancer risk – DES mothers First Author Year RR 95% CI Type of study Greenberg 1984 1.40 1.10-1.90 Incidence Colton 1993 1.35 1.05-1.74 Incidence Calle 1996 1.34 1.06-1.69 Mortality Titus-Ernstroff 2001 1.27 1.07-1.52 Incidence

  12. Endocrine disrupting chemicals–Diethylstilbestrol (DES) • Premenopausal breast cancer risk – DES Daughters First Author Year RR 95% CI Years Follow-up Huckell 1996 Reported 2 cases (28, 34 years of age) Hatch 1998 1.18 0.56 - 2.49 16 years Palmer 2002 1.4 0.7 - 2.6 19 years Palmer 2002 2.5 1.0 - 6.3 in women over 40 Palmer 2002 1.9 0.8 - 4.5 in ER positive tumors

  13. Endocrine disrupting chemicals–Post-menopausal hormone use • Effects on breast cancer risk First Author Year E RR 95% CI E+P RR 95% CI Stanford 1995 0.4 0.20-1.0 Ross 2000 1.06 0.97-1.15 1.24 1.07-1.45 Schairer 2000 1.20 1.00-1.4 1.40 1.10-1.80 Colditz* 2000 1.23 1.06-1.42 1.67 1.18-2.36 Chen 2002 1.17 0.85-1.60 1.49 1.04-2.12 WHI 2002 1.26 1.00-1.59 Porch 2002 0.96 0.65-1.42 1.37 1.05-1.78 Most studies based on 4-5 years current or recent use * Colditz-Risk at 70 years of age after 10 years of use from 50-60 yrs of age

  14. Post-menopausal hormone use –Breast cancer risk, Nurses Health Study HRT, Estrogen + Prog., 10 yrs ERT, Estrogen unopposed, 10 yrs ERT, Estrogen unopposed, 5 yrs Non-users, solid line Ref: Colditz and Rosner, Am. J. Epid., 152:950-964, 2000

  15. Endocrine disrupting chemicals–Post-menopausal hormone use • Nurses Health Study Ref: Porch et al., Cancer Causes & Control, 13:847-854, 2002 PMH use in 17,835 women aged > 45 years, followed for 5.9 yrs PMH use E RR 95% CI* E+P RR 95% CI* 0.96 0.65-1.42 1.37 1.05-1.78 < 5 yrs 0.96 0.58-1.58 1.11 0.81-1.52 > 5 yrs 0.99 0.65-1.53 1.76 1.29-2.39 Progestin pattern <2 wks/month 1.04 0.74 -1.46 Continuous 1.82 1.34 -2.48 • Breast cancer risk increased in women who used: • Estrogen-progestin PMH therapy for 5 years or more • Continous rather than cyclic progestin combinations

  16. Organochlorines and breast cancer risk –Strength of the evidence • DDE and DDT • Early descriptive studies and one case-control study suggested a positive association between blood / adipose tissue DDE levels and breast cancer risk • Majority of recent, well controlled cohort and case-controlled studies have not demonstrated that levels of DDE predict breast cancer risk in white, western, North American or European white women Ref: Snedeker, Environ. Health Perspec. 109(suppl 1):35-47, 2001 WHO/IPCS, Damstra et. al (ed) Global Assessment EDCs, 2002

  17. DDT and DDE commentary –Possible explanations for lack of an association • Chemical formulation • In white western women, predominate exposure may not be to estrogenic o,p’-DDT found in the insecticide, but to the very weakly estrogenic, anti-androgenic breakdown product, p,p’-DDE found as residues in food • Heavily exposed populations not well studied • Predominate use of DDT in the US was on cotton in the south-eastern. One study of African Americans women from North Carolina suggests positive association of DDE and breast cancer risk • Few studies of breast cancer risk in countries that currently use DDT for malaria control • Critical windows of exposure need evaluation • Little information on whether exposure to DDT during early breast development affects breast cancer risk

  18. Organochlorines and breast cancer risk–Dieldrin • Breast cancer risk, equivocal evidence • Danish studies, Copenhagen City Heart Study • 1) Serum dieldrin associated with breast cancer risk OR 2.05, 95%CI 1.17-3.57 Ref: Høyer et al., Lancet, 352, 1816-20,1998 • 2) Serum dieldrin, p53 mutation status & breast cancer risk OR 3.53, 05% CI 0.70-15.79 Ref: Høyer et al., Breast Cancer Res Treat, 71:59-65, 2002 • American studies,no significant association OR 0.6, 95% CI 0.3-1.3, Cohort of Missouri women Ref: Dorgan et al., Cancer Causes & Control 10:1-11, 1999 OR 1.37, 95% CI 0.60-2.72, Long Island Breast Cancer Study Ref: Gammon et al., Cancer Epidem Biomarkers Prevention 11:686-697, 2002

  19. Organochlorines and breast cancer risk–Dieldrin • Breast cancer survival rates and dieldrin levels • Danish studies,Copenhagen City Heart Study • 1) Breast cancer survival and serum dieldrin RR 2.78, 95% CI 1.38-5.59 Higher rate of death associated with highest blood dieldrin levels Ref: Høyer et al., J Clin Epidemiology, 53:323-330, 2000 • 2) Investigated influence of Estrogen Receptor (ER) status and serum dieldrin on breast cancer survival ER+ RR 2.2, 95% CI 0.9-5.4 ER- RR 1.8, 95% CI 0.3-5.5 Risk of dying not significantly elevated in those with higher serum dieldrin levels, regardless of ER status Ref: Høyer et al., BMC Cancer 1:8, 2001 http://www.biomedcentral.com/1471-2407/1/8

  20. Organochlorines and breast cancer risk–Industrial chemicals • Total polychlorinated biphenyls (PCBs) • Little evidence of increased breast cancer risk • Polymorphisms, Gene-environment interaction • Higher BC risk in sub-group of white American women with elevated PCB levels AND variant in CYP1A1 Ref: Moysich et al., Cancer Ep. Biomarkers Prev. 8:414-4, 1999 • Individual PCB congeners • Difficult to evaluate; estrogenic congeners don’t predominate • Some evidence of increased BC risk with congeners that bind to Ah receptor (mono-ortho-substituted) Ref: Demers et al., Am J. Epidemiology, 155:629-35, 2002 • Possible association with poorer prognosis • Association with larger, poorer grade breast tumors Ref: Woolcott, et al., Cancer Causes Control,12:395-404, 2001

  21. Endocrine disrupting chemicals–Industrial chemicals • Polybrominated diphenyl ethers (PBDP) • Uses - Flame retardant in plastics, textiles, carpets and furniture foam • Production - 40,000 tons / yr globally (1990) • Dietary intake - Nordic areas, 0.2-0.7 micrograms/day • Ecology • Detected in marine life globally • Evidence of human breast milk contamination • Detected in air, drinking water, as food residues Refs: Darnerund et al, Environ Health Perspect 109(suppl 1):49-68, 2001 Christensen and Platz, J Environ Monit 3:543-7, 2001 She et al., Chemosphere 46:697-707, 2002 McDonald, Chemosphere 46:745-55, 2002 Wenning, Chemosphere 46:779-96, 2002

  22. Endocrine disrupting chemicals–Industrial chemicals • Polybrominated diphenyl ethers (PBDP) • Evidence of estrogenicity • Stimulates ER-dependent gene expression in human T47D breast cancer cells • Induces cell proliferation in estrogen-dependent MCF-7 breast tumor cell line • Estrogenicity pf PBDEs decreased as bromination increased • PBDPs agonists for both ER-a and ER-b Refs: Samuelsen et al., Cell Biol Toxicol 17:139-51, 2001 Meerts et al., Environ Health Perspect 109:399-407, 2001

  23. Endocrine disrupting chemicals–Occupational exposures ED Chemical Probable exposure % BC Cases % Controls Nonylphenol 21.5 21.4 Butylbenzylphthalate (BBP) 10.0 13.2 BHA 7.3 9.6 Bisphenol A 9.6 11.6 No significant increases in breast cancer risk • PCBs, OR = 3.2, 95% CI 0.8-12.2 • 4-octylphenol, OR = 2.9, 95% CI 0.8-10.8 Ref: Aschengrau et al., Am. J. Ind. Med., 34:6-14, 1998

  24. Endocrine disrupting chemicals–Household levels, Cape Cod study Silent Spring Institute Developed methodology to assess levels of pesticides,bisphenol A, alkylphenols, PAHs, and PCBs in air and dust of residences (microgram/g dust) Chemical No Detect/No Anal Range Mean DEHP 6/6 69.4-524.0 315.0 BBP 6/6 12.1-524 184.0 Carbaryl 2/6 27.2-140 83.6 Chlorpyrifos 3/6 1.26-89.5 30.7 Bisphenol A 3/6 0.25-0.48 0.4 4-Nonylphenol 4/6 2.3-7.82 4.3 Benzo(a)pryrene 5/6 0.45-10.6 2.9 Ref: Rudel et. al., J. Air & Waste Mang. Assoc., 51: 499-513, 2001

  25. Endocrine disrupting chemicals–Effects on early breast development • Premature Thelarche in Puerto Rico (PR) • Over 5,000 cases of premature thelarche in the last 30 years (breast development < 8 yrs of age) • Suspect list: • Waste stream from OCA factories • Hormones residues in food • Ovarian cysts • Use of soy formula • DEHP (phthalate) Ref: Freni-Titulear et al., Am. J. Dis. Children, 140:1263-67, 1986; Colon et al., Environmental Health Perspectives, 108:895-900, 2000

  26. Endocrine disrupting chemicals–Phthalates and Premature Thelarche in Puerto Rican Girls Average conc. in serum, ppb Phthalate esters Ref: Colon et al., Environ Health Perspect, 108:895-900, 2000

  27. Endocrine disrupting chemicals–Premature thelarche and breast cancer risk • More questions than answers • Does occurrence of premature thelarche in girls affect the window of susceptibility of the developing breast to chemical carcinogens? • Do endocrine disrupting chemicals have a role in influencing early breast development? • Research needs • Linkage studies needed between girls with premature thelarche and incidence of breast cancer • Studies needed to assess whether endocrine disrupting chemicals can influence the onset of breast development

  28. Endocrine disrupting chemicals–Industrial contaminants • Dioxins • Seveso Italy, 1976 industrial accident • Breast cancer mortality females,1976-86 RR 0.64, 95%CI 0.4 - 0.9(less than expected) Ref: Bertazzi et al., Am J Epidemiology, 129:1187-1200, 1989 • Seveso Women’s Health Study -Cohort of 981 women, infants to 40 yrsof age in 1976, resided in area of highest TCDD exposure -Preliminary data; those with highest exposures had higher breast cancer risk (15 cases) Ref: Warner et al., Environ Health Perspect 110:625-628, 2002

  29. Endocrine disrupting chemicals-Cellular targets for carcinogens • Terminal End Bud (TEB) • Alveolar Buds Mammary gland structures in the 35-day old CD-1 female mouse Photo: Snedeker and DiAugustine, 1988

  30. Endocrine disrupting chemicals-Understanding susceptibility Human breast development E2 Growth Hormone IGF Ref: Russo and Russo, Oncology Research, 11:169-178, 1999

  31. Endocrine Disrupting Chemicals -Influencing the window of susceptibility • Possible ways in utero or pubertal exposures to EDCs may affect breast cancer risk: • Affecting the expression of hormone or growth factor receptors, and hormone responsiveness of the mammary gland • Lengthening the window of susceptibility by affecting mammary gland development • Persistence of terminal end buds • Influencing differentiation

  32. Endocrine Disrupting Chemicals -Influencing the window of susceptibility • Dioxin - TCDD; effects on mammary gland • TCDD affects ER- a expression • Gestational-lactation exposure to TCDD in rats causes an increase in ER-a expression levels and impaired differentiation in mammary glands of female pups Ref: Lewis et al., Toxicological Sciences 62:46-53, 2001 • TCDD affects cancer susceptibility • Gestational exposure to TCDD causes persistency of TEB structures in female pups, delayed vaginal opening, and an increase in chemically induced (DMBA) mammary adenocarcinomas Ref: Brown et al., Carcinogenesis, 19:1623-1629, 1998 • TCDD permanently affects mammary gland development • Normal mammary gland transplanted into fat pads of TCDD treated female rats grows at a slower rate and appeared underdeveloped; TCDD may affect development of stroma Ref: Fenton et al., Toxicological Sciences, 67:63-74, 2002

  33. Endocrine disrupting chemicals–Heavy metals • Cadmium (Cd), possible estrogenic effects • Interacts with estrogen receptor-alpha (ER-a) MCF-7 cells • Cd binds to ER-a, and blocks binding of estradiol to ER-a • Interacts with hormone binding domain of ER-a • COS-1 cells cotransfected with GAL-ER and GAL4 reporter gene • Treatment with either Cd or estradiol increased reporter gene activity four-fold • ER-a mutants used to identify interaction sites of Cd with ER-a hormone binding domain • In vivo effect on rodent mammary gland • Promotes growth, differentiation and side branching of MG in ovariectomized animal • In utero exposure; earlier onset of puberty; altered MG development Ref: Garcia-Morales et al., J Biol Chem 269:16896-901, 1994 Stocia et al., Molecular Endocrinology, 14:545-553, 2000 Maritin, MB, abstract, e_hormone 2001, Tulane University

  34. Endocrine disrupting chemicals–Heavy metals • Arsenite, possible estrogenic effects • Interacts with estrogen receptor-alpha (ER-a) MCF-7 breast cancer cells treated with arsenite • Decreased level of ER-a and ER-a mRNA • Increased concentration of progesterone receptor (PR) • Arsenite-induced increase in PR blocked by antiestrogens • Arsenite blocked binding of estradiol to ER-a • Stimulates proliferation in MCF-7 cells • Arsenite stimulated proliferation of MCF-7 cells in estrogen depleted medium; effect blocked by antiestrogens • Interacts with hormone binding domain of ER-a • COS-1 cells transfected with GAL-ER and CAT reporter • Arsenite or estradiol treatment induced CAT activity • ER-a mutants used to identify interaction sites of arsenite with ER-a hormone binding domain Ref: Stocia et al., Endocrinology, 141:3595-3602, 2000

  35. Endocrine disrupting chemicals–Current challenges • Complexity of breast cancer • Long latency • Many established risk factors • Risk influenced by interaction of genetic alterations, susceptibility and proliferative state

  36. Endocrine disrupting chemicals–Current challenges • Exposure issues • Difficult to characterize and measure low-level exposures to multiple chemicals from the distant past • Few chemicals have validated biomarkers • Levels of exposure to EDCs at critical periods of breast development (in utero through puberty) is lacking • Exposures to EDCs in the home environment not well characterized

  37. Endocrine disrupting chemicals–Current challenges • Modeling issues • May be difficult to evaluate effects of low-level exposures to multiple chemicals using epidemiology • Animal modeling should include promotional models to assess effects of EDCs that may influence growth of established hormone-dependent tumors • Estrogenicity should not be the sole endpoint for EDC breast cancer risk evaluation; other hormones, growth factor agonists, and chemicals that affect mammary gland development should be evaluated

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