Genetic Bases of Estrogen-Induced Tumorigenesis in the Rat: Mapping of Loci Controlling Susceptibility to Mammary Cancer in a Brown Norway × ACI Intercross

Abstract

Exposure to estrogens is associated with an increased risk of breast cancer. Our laboratory has shown that the ACI rat is uniquely susceptible to 17B-estradiol (E2)-induced mammary cancer. We previously mapped two loci, Emca1 and Emca2 (estrogen-induced mammary cancer), that act independently to determine susceptibility to E2-induced mammary cancer in crosses between the susceptible ACI rat strain and the genetically related, but resistant, Copenhagen (COP) rat strain. In this study, we evaluate susceptibility to E2-induced mammary cancer in a cross between the ACI strain and the unrelated Brown Norway (BN) rat strain. Whereas nearly 100% of the ACI rats developed mammary cancer when treated continuously with E2, BN rats did not develop palpable mammary cancer during the 196-day course of E2 treatment. Susceptibility to E2-induced mammary cancer segregated as a dominant or incompletely dominant trait in a cross between BN females and ACI males. In a population of 251 female (BN Â ACI)F 2 rats, we observed evidence for a total of five genetic determinants of susceptibility. Two loci, Emca4 and Emca5, were identified when mammary cancer status at sacrifice was evaluated as the phenotype, and three additional loci, Emca6, Emca7, and Emca8, were identified when mammary cancer number was evaluated as the phenotype. A total of three genetic interactions were identified. These data indicate that susceptibility to E2-induced mammary cancer in the BN Â ACI cross behaves as a complex trait controlled by at least five loci and multiple gene-gene interactions. (Cancer Res 2006; 66(15): 7793-800)

Estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping

“…To determine whether long-term environmental exposure to estrogen-like chemicals can initiate this epigenetic repression (Fenton 2006;Ho et al 2006;Schaffer et al 2006;Dolinoy et al 2007), progenitor-containing mammospheres were exposed to E2, DES, daidzein, 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), 4-nonylphenol (NP), N-butyl-benzyl phthalate (BBP), di(2-ethylhexyl)-phthalate (DEHP), 4,49-dichloro-biphnyl (PCB), and bisphenol A (BPA) for 3 wk (see the treatment dosages in Fig. 4 legend).…”

Genetic variation in sensitivity to estrogens and breast cancer risk

“…A total of 9 QTL (designated Emca ) influencing susceptibility to mammary tumors (latency and/or number of mammary tumors) were identified (Figure 1). QTL mapped to rat chromosomes 5 and 18 in 17β-estradiol-treated F2 progeny generated in intercrosses between ACI and COP rats and chromosomes 2, 3, 4, 5, 6, 7, and 18 in progeny from intercrosses between ACI and BN rats (Gould et al 2004; Schaffer et al 2006; Shull 2007). The existence of each of these mammary tumor QTL has been confirmed through generation and characterization of congenic rat strains.…”

Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats

“…[44][45][46][47][48] Considering that few other rat strains exhibit this propensity to develop mammary cancer in response to continuous E 2 treatment, it appears that the ACI rat possesses a unique genetic and epigenetic background that underlies its susceptibility to elevated estrogen levels. [49][50][51] Furthermore, the ACI rat has low levels of spontaneous and radiation-induced mammary tumors, thus it is an ideal model to analyze the combined effects of radiation and estrogen.…”