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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 l.jpg

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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Presented at the:

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


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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


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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 cancer

    Ref: Lichtenstein et al., New England J of Medicine, 343:78-85, 2000


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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

???


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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


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Endocrine disrupting chemicals –Possible modes of action

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 / 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


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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 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


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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, American J Epidemiology, 152:950-964, 2000


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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 Study

      Ref: 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 1.38-5.59

        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


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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 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


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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 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


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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-a and ER-b

        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 % 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


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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


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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

Average conc. in serum, ppb

Phthalate esters

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 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., 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

Human breast development

E2

Growth Hormone

IGF

Ref: Russo and Russo, Oncology Research, 11:169-178, 1999


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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- 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


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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

        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-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


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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