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Jump to first page7 Dec. 2002 S. Snedeker
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)
http://www.cfe.cornell.edu/bcerf/
Jump to first page7 Dec. 2002 S. Snedeker
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:
Jump to first page7 Dec. 2002 S. Snedeker
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 diseaseRef: Rockhill et al., American J Epidemiology, 147:826-33, 1998
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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 cancerRef: Lichtenstein et al., New England J of Medicine, 343:78-85, 2000
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Risks Related to Breast Cancer
AdvancingAdvancingAgeAge
GeneticsGenetics
AlcoholAlcohol HormoneHormoneTherapyTherapy
GenderGender
CloseCloseRelativeRelative
Benign Breast Benign Breast DiseaseDisease
EarlyEarlyMenarcheMenarche
Age atAge atFirst BirthFirst Birth PassivePassive
SmokeSmoke
Education Education & & IncomeIncome
OverweightOverweight
(post-menopause)(post-menopause) Lack of Lack of ExerciseExercise
ChemicalsChemicals
--WorkWork
-Home-Home
-Garden-Garden
-Recreation-Recreation
LateLateMenopauseMenopause Breast Breast
FeedingFeeding
??????
DietDiet
IonizingIonizingRadiationRadiation
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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
Jump to first page7 Dec. 2002 S. Snedeker
Endocrine disrupting chemicals–Possible modes of action
Affect hormone levels- Es trogen mimic (additive / syn ergist ic)- Alter synt he sis or
degrada tion pa thways
• Increas e rate o f cellproliferation
• Increas e probabili tyofmutations
• Support th e growth ofhormonally responsivetumors
• Act directl y ascarcinogens
Affec t th e developmentof breas t tissue- Hormon e receptors- Stat e o f differentiation
• Affec t hormonalresponsiveness
• Affec t respons e tochemic al carcinogens
Breast cancer risk
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Endocrine disrupting chemicals
Pharmaceuticals Pesticides Industrial Chemicals / Contaminants Heavy Metals
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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
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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
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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 / 1979Ref: Calle et al., Am J Epidemiology, 144:645-52, 1996
DHEW, US FDA Judge Davidson brief, 1978
Huckell et al., Lancet, 348:331-1996
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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
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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
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Endocrine disrupting chemicals–Post-menopausal hormone use
Effects on breast cancer riskFirst 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
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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
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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
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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
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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
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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 StudyRef: Gammon et al., Cancer Epidemiology Biomarkers & Prevention,
11:686-697, 2002
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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 1.38-5.59Higher 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 statusRef: Høyer et al., BMC Cancer 1:8, 2001 http://www.biomedcentral.com/1471-2407/1/8
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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 CYP1A1Ref: 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
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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 residuesRefs: 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
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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
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Endocrine disrupting chemicals–Occupational exposures
ED Chemical Probable exposure % BC Cases %
ControlsNonylphenol 21.5 21.4Butylbenzylphthalate (BBP) 10.0 13.2BHA 7.3 9.6Bisphenol 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
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Endocrine disrupting chemicals–Household levels, Cape Cod study
Silent Spring InstituteDeveloped 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 A3/6 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
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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
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Endocrine disrupting chemicals –Phthalates and Premature Thelarche in Puerto Rican Girls
0
100
200
300
400
500
600
DBP DEP BBP DOP DEHP MEHP Total
ControlsPT Cases
Phthalate esters
Av
era
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co
nc
. in
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, pp
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Ref: Colon et al., Environmental Health Perspectives, 108:895-900, 2000
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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
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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
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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
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Endocrine disrupting chemicals-Understanding susceptibility
Ref: Russo and Russo, Oncology Research, 11:169-178, 1999
E2
Growth Hormone
IGF
Human breast development
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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
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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
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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
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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 domainRef: Stocia et al., Endocrinology, 141:3595-3602, 2000
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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
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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
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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