Genetic variation in sensitivity to DES and breast cancer risk

Extent of variation in responses to DES among strains of rodents

2018 Study 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.

Responses to DES among strains of rodents

…”Long-term exposure to diethylstilbestrol (DES) increased ductal branching to a similar extent in wild type BALB/cJ and 129/SvEv female mice but no mammary tumors were observed in either strain.” …

…”ACI rats also developed mammary tumors with chronic exposure to 17β-estradiol or DES.”…

…”While estrogen agonists induce proliferative responses in mammary, uterine and pituitary, they cause regression in other tissues. DES induced thymic regression in both C57BL/6 and BALB/c strains. Although the strains differed in initial thymus weights, both exhibited similar ~1.5 g decreases following DES treatment. In rats, the F433 strain was most responsive in pituitary and uterine tissues, but DES-induced thymic regression was greatest in the SD strain compared to F344 and BN.”…

… “In contrast, ACI rats have a persistent proliferative response to DES in mammary epithelium without a compensatory increase in apoptosis and was associated with extensive hyperplasia. Thus, strains of rodents appear to have adopted different strategies to achieve tissue homeostasis. The ability to attenuate signaling also appears to differ among tissues. An example is the formation of neoplastic lesions in the uterus of 129/SvEv mice treated with DES, but no lesions developed in the mammary glands of these mice.”…

Genetic variants determining responses to DES

…”When pituitary weight was used as a phenotypic indicator of estrogen stimulated lactotroph proliferation, five QTL were identified upon characterization of DES treated female F2 progeny generated in an intercross between F344 and BN rats. One additional QTL was mapped during characterization of backcross progeny generated using these same strains. When ACI rats were utilized as the sensitive strain, six QTL were mapped upon characterization of DES treated male F2 progeny generated in reciprocal intercrosses between ACI and COP rats…”

…”A second QTL, Eutr2 was mapped to the same region of chromosome 5 through characterization of DES treated congenic rats in which BN alleles across proximal chromosome 5 were introgressed onto the F344 genetic background.”…

…”Treatment with DES identified QTL influencing repression on chromosome 10 (Esta1) and chromosome 2 (Esta2 and Esta3) in a study using male F2 progeny from a BN x ACI intercross. QTL associated with regression of testes induced by DES were identified on chromosomes 1 and 7 in recombinant inbred male rats.”…


  • Full study (free access) : Genetic variation in sensitivity to estrogens and breast cancer risk, Mammalian genome : official journal of the International Mammalian Genome Society, NCBI PubMed PMC5936622, 2018 Feb 29.
  • Positions of QTL regulated responses to estrogens in 5 tissues in rats featured image credit figure/F1.

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