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Grant Details

Grant Number: 5U01ES026140-05 Interpret this number
Primary Investigator: Jerry, D.
Organization: University Of Massachusetts Amherst
Project Title: Disruption of Parity-Induced Tumor Suppressor Pathways By Xenoestrogen Exposures
Fiscal Year: 2019


Abstract

 DESCRIPTION (provided by applicant): Parity engages pathways within the breast epithelium that render it resistant to carcinogenesis. These pathways are potent as parity reduces the risk associated with carcinogens and inherited risk alleles preventing as many as 70,000 cases of breast cancer annually. The levels of estrogens during pregnancy are sufficient to mimic the protective effects of parity. The actions of estrogens are mediated by two estrogen receptor subtypes (ERα and ERβ) that balance their competing effects on proliferation and growth suppression mediated by the p53 tumor suppressor pathway. Pregnancy also suppresses WNT/β-catenin signaling and reduces the pool of vulnerable stem cells within the mammary epithelium. However, chronic exposure to exogenous estrogens erodes the protective effects of pregnancy in rodents. During pregnancy, women are exposed to high levels of xenoestrogens (benzophenones, parabens, phthalates) that differ in their potencies for ERα and ERβ. Therefore, pregnancy is a critical window during which xenoestrogens may disrupt tumor suppressor pathways and render the breast epithelium susceptible to carcinogenesis. In these experiments, we will test 4 xenoestrogens that are abundant in pregnant women and differ in potency for ERα and ERβ. Parallel experiments in primary breast tissues and mouse models are used to determine if xenoestrogens interfere with the effects of pregnancy on critical tumor suppressor pathways. Specific Aim 1 will use breast epithelial cells to determine the effects of xenoestrogens on tumor suppressor pathways and the variation in responses among women. Dose-response relationships for each xenoestrogen will be determined in MCF-7 breast cancer cells expressing either ERα or both ERα+ERβ. Primary cultures of normal breast epithelial cells will be used to confirm responses and define subsets of women who are highly sensitive or resistant to xenoestrogens. Specific Aim 2 compares effects of xenoestrogens in explant cultures of breast tissue and in BALB/c mice. Primary breast explants more faithfully reflect signaling within breast tissue and complement results from Aim 1. Parallel treatments in mice that are particularly sensitive to estrogens (BALB/c) will validate the in vivo model and determine effects of chronic exposures to xenoestrogens on tumor suppressor pathways. Specific Aim 3 will test the effects of xenoestrogens on tumorigenesis. The ability of xenoestrogens to cause progression of premalignant cells will be tested using transplants of CDβGeo cells. The ability of xenoestrogens to reverse the protective effect of parity will be tested in mice bearing transplants of Trp53+/- mammary epithelium. Community Engagement: The Community Partners provide a means to dynamically communicate the concerns of the community and results from research. Importantly, the experiments are designed to identify a subset of women who may be especially vulnerable to xenoestrogens and demonstrate the relevance of the mouse models to human exposures.



Publications

Genetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndrome.
Authors: Majhi P.D. , Griner N.B. , Mayfield J.A. , Compton S. , Kane J.J. , Baptiste T.A. , Dunphy K.A. , Roberts A.L. , Schneider S.S. , Savage E.M. , et al. .
Source: Oncogene, 2021 Aug; 40(31), p. 5026-5037.
EPub date: 2021-06-28.
PMID: 34183771
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Exposure to Propylparaben During Pregnancy and Lactation Induces Long-Term Alterations to the Mammary Gland in Mice.
Authors: Mogus J.P. , LaPlante C.D. , Bansal R. , Matouskova K. , Schneider B.R. , Daniele E. , Silva S.J. , Hagen M.J. , Dunphy K.A. , Jerry D.J. , et al. .
Source: Endocrinology, 2021-06-01; 162(6), .
PMID: 33724348
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The science of spin: targeted strategies to manufacture doubt with detrimental effects on environmental and public health.
Authors: Goldberg R.F. , Vandenberg L.N. .
Source: Environmental health : a global access science source, 2021-03-26; 20(1), p. 33.
EPub date: 2021-03-26.
PMID: 33771171
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Update on the Health Effects of Bisphenol A: Overwhelming Evidence of Harm.
Authors: Vom Saal F.S. , Vandenberg L.N. .
Source: Endocrinology, 2021-03-01; 162(3), .
PMID: 33516155
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Assessing the Public Health Implications of the Food Preservative Propylparaben: Has This Chemical Been Safely Used for Decades.
Authors: Vandenberg L.N. , Bugos J. .
Source: Current environmental health reports, 2021 03; 8(1), p. 54-70.
EPub date: 2021-01-08.
PMID: 33415721
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Agrochemicals with estrogenic endocrine disrupting properties: Lessons Learned?
Authors: Vandenberg L.N. , Najmi A. , Mogus J.P. .
Source: Molecular and cellular endocrinology, 2020-12-01; 518, p. 110860.
EPub date: 2020-05-12.
PMID: 32407980
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The Mouse Mammary Gland: a Tool to Inform Adolescents About Environmental Causes of Breast Cancer.
Authors: Vandenberg L.N. , Kolla S. , LaPlante C.D. , Jerry D.J. .
Source: Journal of cancer education : the official journal of the American Association for Cancer Education, 2020 12; 35(6), p. 1094-1100.
PMID: 31227995
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The Use and Misuse of Historical Controls in Regulatory Toxicology: Lessons from the CLARITY-BPA Study.
Authors: Vandenberg L.N. , Prins G.S. , Patisaul H.B. , Zoeller R.T. .
Source: Endocrinology, 2020-05-01; 161(5), .
PMID: 31690949
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There are good clinical, scientific, and social reasons to strengthen links between biomedical and environmental research.
Authors: Porta M. , Vandenberg L.N. .
Source: Journal of clinical epidemiology, 2019 07; 111, p. 124-126.
EPub date: 2019-03-21.
PMID: 30905697
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Gene expression signature of atypical breast hyperplasia and regulation by SFRP1.
Authors: Gregory K.J. , Roberts A.L. , Conlon E.M. , Mayfield J.A. , Hagen M.J. , Crisi G.M. , Bentley B.A. , Kane J.J. , Makari-Judson G. , Mason H.S. , et al. .
Source: Breast cancer research : BCR, 2019-06-27; 21(1), p. 76.
EPub date: 2019-06-27.
PMID: 31248446
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Asymmetric development of the male mouse mammary gland and its response to a prenatal or postnatal estrogen challenge.
Authors: Pokharel A. , Kolla S. , Matouskova K. , Vandenberg L.N. .
Source: Reproductive toxicology (Elmsford, N.Y.), 2018 12; 82, p. 63-71.
EPub date: 2018-10-11.
PMID: 30315872
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Sterilization of Silastic Capsules Containing 17β-Estradiol for Effective Hormone Delivery in Mus musculus.
Authors: Majewski A.R. , Chuong L.M. , Neill H.M. , Roberts A.L. , Jerry D.J. , Dunphy K.A. .
Source: Journal of the American Association for Laboratory Animal Science : JAALAS, 2018-10-12; , .
EPub date: 2018-10-12.
PMID: 30314533
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Oxybenzone Alters Mammary Gland Morphology in Mice Exposed During Pregnancy and Lactation.
Authors: LaPlante C.D. , Bansal R. , Dunphy K.A. , Jerry D.J. , Vandenberg L.N. .
Source: Journal of the Endocrine Society, 2018-08-01; 2(8), p. 903-921.
EPub date: 2018-05-22.
PMID: 30057971
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'No Pink Ribbons': How Women's Lived Experiences With Breast Atypia Inform Decisions Involving Risk-Reducing Medications.
Authors: Goff S.L. , Kleppel R. , Makari-Judson G. .
Source: Journal of patient-centered research and reviews, 2018 Spring; 5(2), p. 158-166.
EPub date: 2018-04-26.
PMID: 31414000
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Genetic variation in sensitivity to estrogens and breast cancer risk.
Authors: Jerry D.J. , Shull J.D. , Hadsell D.L. , Rijnkels M. , Dunphy K.A. , Schneider S.S. , Vandenberg L.N. , Majhi P.D. , Byrne C. , Trentham-Dietz A. .
Source: Mammalian genome : official journal of the International Mammalian Genome Society, 2018 02; 29(1-2), p. 24-37.
EPub date: 2018-02-27.
PMID: 29487996
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Individual-specific variation in the respiratory activities of HMECs and their bioenergetic response to IGF1 and TNFα.
Authors: Schneider S.S. , Henchey E.M. , Sultana N. , Morin S.M. , Jerry D.J. , Makari-Judson G. , Crisi G.M. , Arenas R.B. , Johnson M. , Mason H.S. , et al. .
Source: Journal of cellular physiology, 2017 Oct; 232(10), p. 2750-2765.
EPub date: 2017-05-15.
PMID: 28369883
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