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

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

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

  • 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/
  • 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:
  • 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
  • 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
  • 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
  • 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
  • Endocrine disrupting chemicals – Possible modes of action Breast cancer risk
  • Endocrine disrupting chemicals
    • Pharmaceuticals
    • Pesticides
    • Industrial Chemicals / Contaminants
    • Heavy Metals
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Endocrine disrupting chemicals -Understanding susceptibility Ref: Russo and Russo, Oncology Research, 11:169-178, 1999 E2 Growth Hormone IGF Human breast development
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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