Genetic variation in sensitivity to estrogens and breast cancer risk

D Joseph Jerry^{1

2}, James D Shull^{3

4}, Darryl L Hadsell^{5

6}, Monique Rijnkels⁷, Karen A Dunphy⁸, Sallie S Schneider⁹, Laura N Vandenberg¹⁰, Prabin Dhangada Majhi⁸, Celia Byrne¹¹, Amy Trentham-Dietz¹²

Affiliations

¹ Department of Veterinary & Animal Sciences, 661 North Pleasant Street, Integrated Life Sciences Building, Amherst, MA, 01003, USA. jjerrry@vasci.umass.edu.
² Pioneer Valley Life Sciences Institute, Baystate Medical Center, 3601 Main Street, Springfield, MA, 01199, USA. jjerrry@vasci.umass.edu.
³ Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA.
⁴ UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53705, USA.
⁵ Department of Pediatrics, USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA.
⁶ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
⁷ Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843, USA.
⁸ Department of Veterinary & Animal Sciences, 661 North Pleasant Street, Integrated Life Sciences Building, Amherst, MA, 01003, USA.
⁹ Pioneer Valley Life Sciences Institute, Baystate Medical Center, 3601 Main Street, Springfield, MA, 01199, USA.
¹⁰ Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, 01003, USA.
¹¹ Department of Preventive Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
¹² Department of Population Health Sciences and the Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.

PMID: 29487996
PMCID: PMC5936622
DOI: 10.1007/s00335-018-9741-z

Review

Genetic variation in sensitivity to estrogens and breast cancer risk

D Joseph Jerry et al. Mamm Genome. 2018 Feb.

. 2018 Feb;29(1-2):24-37.

doi: 10.1007/s00335-018-9741-z. Epub 2018 Feb 27.

Authors

Affiliations

¹ Department of Veterinary & Animal Sciences, 661 North Pleasant Street, Integrated Life Sciences Building, Amherst, MA, 01003, USA. jjerrry@vasci.umass.edu.
² Pioneer Valley Life Sciences Institute, Baystate Medical Center, 3601 Main Street, Springfield, MA, 01199, USA. jjerrry@vasci.umass.edu.
³ Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA.
⁴ UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53705, USA.
⁵ Department of Pediatrics, USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA.
⁶ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
⁷ Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843, USA.
⁸ Department of Veterinary & Animal Sciences, 661 North Pleasant Street, Integrated Life Sciences Building, Amherst, MA, 01003, USA.
⁹ Pioneer Valley Life Sciences Institute, Baystate Medical Center, 3601 Main Street, Springfield, MA, 01199, USA.
¹⁰ Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, 01003, USA.
¹¹ Department of Preventive Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
¹² Department of Population Health Sciences and the Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.

PMID: 29487996
PMCID: PMC5936622
DOI: 10.1007/s00335-018-9741-z

Abstract

Breast cancer risk is intimately intertwined with exposure to estrogens. While more than 160 breast cancer risk loci have been identified in humans, genetic interactions with estrogen exposure remain to be established. Strains of rodents exhibit striking differences in their responses to endogenous ovarian estrogens (primarily 17β-estradiol). Similar genetic variation has been observed for synthetic estrogen agonists (ethinyl estradiol) and environmental chemicals that mimic the actions of estrogens (xenoestrogens). This review of literature highlights the extent of variation in responses to estrogens among strains of rodents and compiles the genetic loci underlying pathogenic effects of excessive estrogen signaling. Genetic linkage studies have identified a total of the 35 quantitative trait loci (QTL) affecting responses to 17β-estradiol or diethylstilbestrol in five different tissues. However, the QTL appear to act in a tissue-specific manner with 9 QTL affecting the incidence or latency of mammary tumors induced by 17β-estradiol or diethylstilbestrol. Mammary gland development during puberty is also exquisitely sensitive to the actions of endogenous estrogens. Analysis of mammary ductal growth and branching in 43 strains of inbred mice identified 20 QTL. Regions in the human genome orthologous to the mammary development QTL harbor loci associated with breast cancer risk or mammographic density. The data demonstrate extensive genetic variation in regulation of estrogen signaling in rodent mammary tissues that alters susceptibility to tumors. Genetic variants in these pathways may identify a subset of women who are especially sensitive to either endogenous estrogens or environmental xenoestrogens and render them at increased risk of breast cancer.

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Figures

**Figure 1. Positions of QTL regulated responses to estrogens in 5 tissues in rats**
The phenotypes and strains used to define the quantitative trait loci (QTL) are indicated. The localization of QTL is based on the polymorphic markers used in mapping experiments. An interval is indicated using a horizontal line for *Emca1* and *Eutr2*.

See this image and copyright information in PMC

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Genetic variation in sensitivity to estrogens and breast cancer risk

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Genetic variation in sensitivity to estrogens and breast cancer risk

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