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 17beta-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 x 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 x ACI cross behaves as a complex trait controlled by at least five loci and multiple gene-gene interactions.
Highlights
Breast cancer is the most frequently diagnosed nonskin cancer and the second leading cause of cancer-related death in American women
Data presented indicate that the inbred ACI and Brown Norway (BN) rat strains differ markedly with respect to susceptibility to E2-induced mammary cancer, and that susceptibility of F2 progeny produced in an intercross originating with BN females and ACI males is determined by at least five Emca loci
ACI alleles for Emca4, Emca5, Emca6, and Emca8, which map to RNO7, RNO3, RNO4, and RNO5, respectively, were associated with increased susceptibility to E2induced mammary cancer, whereas the ACI allele for Emca7, which maps to RNO6, was associated with reduced susceptibility
Summary
Breast cancer is the most frequently diagnosed nonskin cancer and the second leading cause of cancer-related death in American women. The lifetime risk of a woman in the United States developing breast cancer is approaching one in seven. Numerous studies implicate estrogens in the etiology of breast cancer [1,2,3,4]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). This article is part of a series of articles describing genetic control of estrogen action in various organ systems in the rat, including the pituitary gland, mammary gland, and uterus.
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