Genetic variation in sensitivity to estrogens and breast cancer risk

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 5 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.

Sterilization of Silastic Capsules Containing 17β-Estradiol for Effective Hormone Delivery in Mus musculus

“…In addition, variation in responses to estrogens among rodent strains should be considered. 11 Although our results show that the serum E2 on day 14 did not differ between nonsterilized capsules and those sterilized with 5-kGy IR, γ irradiation could affect the secretion rates of some capsule materials and matrices. 16 Our objective with the hormone treatments is to mimic pregnancy-induced changes in the mammary gland.…”

MiR-181c affects estrogen-dependent endometrial carcinoma cell growth by targeting PTEN

“…Estrogens regulate many functions, for example, female reproductive system, cardiovascular system, nervous system, bone excretory system and immune response, in human organism [24]. Estrogens play a major role in physiological changes or pathological changes, including endometrial carcinoma, breast cancer, ovarian cancer and other tumors, in women [9,25,26]. Estradiol (E2) is the main component of estrogen.…”

Ept7, a quantitative trait locus that controls estrogen-induced pituitary lactotroph hyperplasia in rat, is orthologous to a locus in humans that has been associated with numerous cancer types and common diseases

“…Ept7 is one of 19 QTL that have been linked to estrogen-induced increases in pituitary weight, a well-defined surrogate phenotype for lactotroph hyperplasia/adenoma [ 28 , 30 , 33 , 34 , 51 ]. Data presented in this manuscript refine the location of Ept7 to a 1.91 Mb interval on RNO7.…”