Genetic Susceptibility of Estrogen Induced Mammary CA

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DESCRIPTION (provided by applicant): Although numerous epidemiologic, clinical and laboratory studies inextricably link estrogens to the etiology of breast cancer, the mechanism(s) through which estrogens contribute to breast cancer development remain largely unknown. Our laboratory has demonstrated that the ACI rat is unique from most other inbred rat strains in its unique propensity to develop mammary carcinoma when treated continuously with the naturally occurring estrogen, 17beta-estradiol (E2). Whereas mammary cancer incidence following 28 weeks of E2 treatment is virtually 100% in female ACI rats, incidence in the genetically related Copenhagen (COP) and unrelated Brown Norway (BN) strains is 20% and 0% respectively. The ACI phenotype segregates in an incompletely dominant and dominant manner in crosses to COP and BN. We have mapped four loci, Emca1 through 4, which confer, at least in part, this unique susceptibility. Aim 1 is to characterize a series of congenic rat lines in which the susceptibility conferring ACI alleles of Emca1, Emca2 and/or Emca3 have been replaced by alleles from the resistant COP or BN rat strains. We hypothesize that: 1) rats carrying COP or BN alleles at one or more of the Emca loci will exhibit reduced susceptibility to E2-induced mammary cancer, relative to the ACI strain; and 2) each Emca locus may selectively impact different mammary cancer associated phenotypes. Aim 2 is to develop and characterize a congenic rat line for Emca4. Aim 3 is to fine map each Emca locus to establish more precisely the locations of the genes that confer and/or modify susceptibility to E2-induced mammary cancer. Aim 4 is to define the association between allelic imbalances within the Emca loci and E2-induced mammary carcinogenesis. The hypothesis to be tested is that regions of the genome harboring genes that contribute to E2-induced mammary cancer, including the Emca loci, will exhibit allelic imbalances at a rate above that of the genome at large. Aim 5 is to examine E2-induced mammary carcinogenesis in an ACI-derived congenic rat line that exhibits a significantly reduced propensity to develop E2-induced pituitary tumors and associated hyperprolactinemia. The hypothesis to be tested is that E2-induced mammary carcinogenesis and pituitary tumorigenesis are independent and genetically separable events. The studies proposed in this renewal application will provide mechanistic information relating to the roles of estrogens and the Emca loci in mammary cancer etiology, provide the foundation for efforts to identify these mammary cancer susceptibility genes and further validate the ACI rat as a novel model of E2-induced mammary carcinogenesis that is highly relevant to human breast cancer.