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Breast Cancer - Is there a link to endocrine disrupting chemicals? Breast Cancer - Is there a link to endocrine disrupting chemicals?

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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) [email_address] http://www.cfe.cornell.edu/bcerf/
    • 2. 2nd Copenhagen Workshop on Endocrine Disrupters: A Possible Role of Mixed Exposures for Reproductive Failures and Malignancies Session 1: EDC Effects in Humans December 7th, 2002 Rigshospitalet (Copenhagen University Hospital) Copenhagen, Denmark Presented at the:
    • 3. 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 National Cancer Institute, 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., American J Epidemiology, 147:826-33, 1998
    • 4. 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
    • 5. Risks Related to Breast Cancer Advancing Age Genetics Alcohol Hormone Therapy Gender Close Relative Benign Breast Disease Early Menarche Age at First Birth Passive Smoke Education & Income Overweight (post-menopause) Lack of Exercise Chemicals - Work -Home -Garden -Recreation Late Menopause Breast Feeding ??? Diet Ionizing Radiation
    • 6. Endocrine disrupting chemicals – Definitions
      • Endocrine Disrupter
        • 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 Disrupter
        • 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
    • 7. Endocrine disrupting chemicals – Possible modes of action Breast cancer risk
    • 8. Endocrine disrupting chemicals
      • Pharmaceuticals
      • Pesticides
      • Industrial Chemicals / Contaminants
      • Heavy Metals
    • 9. 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 Biology and Neoplasia, 7:93-105, 2002
    • 10. 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 National Cancer Institute, 88:71-6, 1997
    • 11. 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
    • 12. 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
    • 13. 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
    • 14. 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
    • 15. Post-menopausal hormone use – Breast cancer risk, Nurses Health Study Ref: Colditz and Rosner, American J Epidemiology, 152:950-964, 2000 HRT, Estrogen + Prog., 10 yrs ERT, Estrogen unopposed, 10 yrs ERT, Estrogen unopposed, 5 yrs Non-users, solid line
    • 16. 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
        • Continuous rather than cyclic progestin combinations
    • 17. 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, Environmental Health Perspectives, 109(suppl 1):35-47, 2001
        • WHO/IPCS, Damstra et. al. (ed) Global Assessment EDCs, 2002
    • 18. 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
    • 19. 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 Research and Treatment, 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 Epidemiology Biomarkers & Prevention,
          • 11:686-697, 2002
    • 20. 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 Clinical 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
    • 21. 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 Epidemiology Biomarkers & Prevention,
          • 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., American 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
    • 22. 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, Environmental Health Perspectives, 109(suppl 1):49-68, 2001
          • Christensen and Platz, J Environmental Monitoring, 3:543-7, 2001
          • She et al., Chemosphere 46:697-707, 2002
          • McDonald, Chemosphere 46:745-55, 2002
          • Wenning, Chemosphere 46:779-96, 2002
    • 23. 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 of PBDEs decreased as bromination increased
          • PBDPs agonists for both ER-  and ER- 
          • Refs: Samuelsen et al., Cell Biology and Toxicology, 17:139-51, 2001
          • Meerts et al., Environmental Health Perspectives, 109:399-407, 2001
    • 24. 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., American J Industrial Medicine, 34:6-14, 1998
    • 25. 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 Management Assoc., 51: 499-513, 2001
    • 26. 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
    • 27. Endocrine disrupting chemicals – Phthalates and Premature Thelarche in Puerto Rican Girls Phthalate esters Average conc. in serum, ppb Ref: Colon et al., Environmental Health Perspectives, 108:895-900, 2000
    • 28. 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
    • 29. 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 yrs of 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., Environmental Health Perspectives, 110:625-628, 2002
    • 30. 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
    • 31. Endocrine disrupting chemicals -Understanding susceptibility Ref: Russo and Russo, Oncology Research, 11:169-178, 1999 E2 Growth Hormone IGF Human breast development
    • 32. 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
    • 33. Endocrine Disrupting Chemicals - Influencing the window of susceptibility
      • Dioxin - TCDD; effects on mammary gland
        • TCDD affects ER-  expression
          • Gestational-lactation exposure to TCDD in rats causes an increase in ER-  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
    • 34. Endocrine disrupting chemicals –Heavy metals
      • Cadmium (Cd), possible estrogenic effects
        • Interacts with estrogen receptor-alpha (ER-  ) MCF-7 cells
          • Cd binds to ER-  and blocks binding of estradiol to ER- 
        • Interacts with hormone binding domain of ER- 
          • COS-1 cells cotransfected with GAL-ER and GAL4 reporter gene
          • Treatment with either Cd or estradiol increased reporter gene activity four-fold
          • ER-  mutants used to identify interaction sites of Cd with ER-  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
          • Refs: Garcia-Morales et al., J Biological Chemistry, 269:16896-901, 1994
          • Stocia et al., Molecular Endocrinology, 14:545-553, 2000
          • Maritin, MB, abstract, e_hormone 2001, Tulane University
    • 35. Endocrine disrupting chemicals –Heavy metals
      • Arsenite, possible estrogenic effects
        • Interacts with estrogen receptor-alpha (ER-  )
          • MCF-7 breast cancer cells treated with arsenite
          • Decreased level of ER-  and ER-  mRNA
          • Increased concentration of progesterone receptor (PR)
          • Arsenite-induced increase in PR blocked by antiestrogens
          • Arsenite blocked binding of estradiol to ER- 
        • 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- 
          • COS-1 cells transfected with GAL-ER and CAT reporter
          • Arsenite or estradiol treatment induced CAT activity
          • ER-  mutants used to identify interaction sites of arsenite with ER-  hormone binding domain
          • Ref: Stocia et al., Endocrinology, 141:3595-3602, 2000
    • 36. 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
    • 37. 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
    • 38. 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