Title: Breast Cancer
1Breast Cancer
- Is there a link to
- Endocrine Disrupting Chemicals?
- Suzanne M. Snedeker, Ph.D.
- Assoc. Director for Translational Research
-
- Cornell Universitys
- Program on Breast Cancer and Environmental
Risk Factors (BCERF) - sms31_at_cornell.edu
- http//www.cfe.cornell.edu/bcerf/
2Presented 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
3Contribution 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,
871681-5, 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,
147826-33, 1998
4Environmental 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, 34378-85, 2000
5Risks 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
???
6Endocrine 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
7Endocrine disrupting chemicals Possible modes
of action
Breast cancer risk
8Endocrine disrupting chemicals
- Pharmaceuticals
- Pesticides
- Industrial Chemicals / Contaminants
- Heavy Metals
9Endocrine 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, 793-105, 2002
10Endocrine disrupting chemicals Ovarian hormones
- In utero exposure to estrogen associated with
higher breast cancer risk - Higher birth weight
- Ref Michels, et al., Lancet, 3481542-46, 1996
- Kaijser et al., Epidemiology, 11315-9,
2000 - Like-sexed female (dizygotic) twins
- Ref Ekbom et al., J Natl Cancer Inst 8871-6,
1997 - Cerhan et al., J Natl Cancer Inst,
92262-5, 2000 - Hubinette et al., Int J Cancer 91248-51,
2001 - Preeclampsia (lower estrogen, lower risk) Ref
Ekbom et al., Lancet, 3401015-18, 1992 - Ekbom et al., J National Cancer
Institute, 8871-6, 1997
11Endocrine disrupting chemicals Diethylstibestero
l (DES)
- DESHistory 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
- DESHistory 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,
144645-52, 1996 - DHEW, US FDA Judge Davidson brief, 1978
- Huckell et al., Lancet, 348331-1996
12Endocrine disrupting chemicals Diethylstilbestro
l (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
13Endocrine disrupting chemicals Diethylstilbestro
l (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
14Endocrine disrupting chemicals Post-menopausal
hormone use
- Effects on breast cancer risk
- First Author Year E RR 95 CI
EP 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
15Post-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,
152950-964, 2000
16Endocrine disrupting chemicals Post-menopausal
hormone use
- Nurses Health Study
- Ref Porch et al., Cancer Causes Control,
13847-854, 2002 - PMH use in 17,835 women aged gt 45 years, followed
for 5.9 yrs - PMH use E RR 95 CI EP RR 95
CI - 0.96 0.65-1.42 1.37 1.05-1.78
- lt 5 yrs 0.96 0.58-1.58 1.11 0.81-1.52
- gt 5 yrs 0.99 0.65-1.53 1.76 1.29-2.39
- Progestin pattern
- lt2 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
17Organochlorines 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
18DDT 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
19Organochlorines 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, 95CI 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, 7159-65, 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
101-11, 1999 - OR 1.37, 95 CI 0.60-2.72, Long Island
Breast Cancer Study - Ref Gammon et al., Cancer Epidemiology
Biomarkers Prevention, - 11686-697, 2002
20Organochlorines 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,
53323-330, 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 18, 2001
http//www.biomedcentral.com/1471-2407/1/8
21Organochlorines 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, - 8414-4, 1999
- Individual PCB congeners
- Difficult to evaluate estrogenic congeners dont
predominate - Some evidence of increased BC risk with congeners
that bind to Ah receptor (mono-ortho-substituted) - Ref Demers et al., American J Epidemiology,
155629-35, 2002 - Possible association with poorer prognosis
- Association with larger, poorer grade breast
tumors - Ref Woolcott, et al., Cancer Causes
Control,12395-404, 2001
22Endocrine 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, 3543-7, 2001 - She et al., Chemosphere 46697-707, 2002
- McDonald, Chemosphere 46745-55, 2002
- Wenning, Chemosphere 46779-96, 2002
23Endocrine 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, 17139-51, 2001 - Meerts et al., Environmental Health
Perspectives, 109399-407, 2001
24Endocrine 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, 346-14, 1998
25Endocrine 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
26Endocrine 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 lt 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,
1401263-67, 1986 - Colon et al., Environmental Health
Perspectives, 108895-900, 2000
27Endocrine disrupting chemicals Phthalates
and Premature Thelarche in Puerto Rican Girls
Average conc. in serum, ppb
Phthalate esters
Ref Colon et al., Environmental Health
Perspectives, 108895-900, 2000
28Endocrine 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
29Endocrine disrupting chemicals Industrial
contaminants
- Dioxins
- Seveso Italy, 1976 industrial accident
- Breast cancer mortality females,1976-86
- RR 0.64, 95CI 0.4 - 0.9 (less than expected)
- Ref Bertazzi et al., Am J Epidemiology,
1291187-1200, 1989 - Seveso Womens 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, 110625-628, 2002
30Endocrine disrupting chemicals -Cellular targets
for carcinogens
Mammary gland structures in the 35-day old CD-1
female mouse
- Terminal End Bud
- (TEB)
- Alveolar Buds
Photo Snedeker and DiAugustine, 1988
31Endocrine disrupting chemicals -Understanding
susceptibility
Human breast development
E2 Growth Hormone IGF
Ref Russo and Russo, Oncology Research,
11169-178, 1999
32Endocrine 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
33Endocrine 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,
6246-53, 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, 191623-1629,
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,
6763-74, 2002
34Endocrine 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, 26916896-901, 1994 - Stocia et al., Molecular Endocrinology,
14545-553, 2000 - Maritin, MB, abstract, e_hormone 2001,
Tulane University
35Endocrine 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,
1413595-3602, 2000
36Endocrine 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
37Endocrine 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
38Endocrine 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