Genetic variation in sensitivity to estrogens and breast cancer risk.

TitleGenetic variation in sensitivity to estrogens and breast cancer risk.
Publication TypeJournal Article
Year of Publication2018
AuthorsD Jerry, J, Shull, JD, Hadsell, DL, Rijnkels, M, Dunphy, KA, Schneider, SS, Vandenberg, LN, Majhi, PDhangada, Byrne, C, Trentham-Dietz, A
JournalMamm Genome
Date Published2018 02
KeywordsAnimals, Breast Neoplasms, Estradiol, Estrogens, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Mammary Glands, Human, Mammary Neoplasms, Animal, Mice, Quantitative Trait Loci, Risk Factors

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.

Alternate JournalMamm Genome
PubMed ID29487996
PubMed Central IDPMC5936622
Grant ListR01-CA77876 / / Division of Cancer Epidemiology and Genetics, National Cancer Institute / International
U01ES026127 / ES / NIEHS NIH HHS / United States
R01 CA204320 / CA / NCI NIH HHS / United States
U01 ES026127 / ES / NIEHS NIH HHS / United States
W81XWH-15-1-0217 / / U.S. Department of Defense / International
U01 ES026132 / ES / NIEHS NIH HHS / United States
U01 ES026140 / ES / NIEHS NIH HHS / United States
R01 CA077876 / CA / NCI NIH HHS / United States
U01ES026140 / ES / NIEHS NIH HHS / United States
6250-51000-052 / / Agricultural Research Service / International
R01-CA204320 / CA / NCI NIH HHS / United States
U01ES026132 / ES / NIEHS NIH HHS / United States