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

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Jump to first page 7 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) [email protected] http://www.cfe.cornell.edu/bcerf/
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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)

[email protected]

http://www.cfe.cornell.edu/bcerf/

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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:

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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 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

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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

ge

co

nc

. in

se

rum

, pp

b

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


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