GENETIC SUSCEPTIBILITY TO ESTROGEN INDUCED MAMMARY CA

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DESCRIPTION: (adapted from the investigator's abstract) The investigators have recently demonstrated that ovary-intact, but not ovariectomized, female ACI rates treated continually with near physiologic levels of the naturally occurring estrogen, 17b-estradiol (ES2), rapidly develop multiple and often invasive mammary carcinomas. More recently, they have examined induction by E2 of mammary carcinoma in F1, F2 and backcross (BC) progeny of a genetic cross between females of t he highly susceptible ACI inbred strain and males of a resistant inbred strain, Copenhagen (COP). The data from this experiment closely fit models in which susceptibility to E2 -induced mammary cancers is conferred by the dominantly acting ACI allele of a single gene, referred to as EMCA-1 (Estrogen-induced Mammary Cancer-1) Moreover, it appears that the dominantly acting COP allele of an independently segregating gene, referred to as MCS-X (Mammary cancer suppressor-X), may act to delay development of mammary carcinomas in E2 treated progeny. These data provide the first evidence that susceptibility to E2 -induced mammary cancers in any species behaves as a relatively simple Mendelian trait conferred and/or modulated through the actions of limited number of genes. Because of the well documented role of estrogens in etiology of breast cancer in humans, the ACI rat appears to represent a unique and highly relevant animal model for the study of this disease. The hypotheses underlying the research proposed herein are: 1)EMCA-1 is necessary and sufficient to confer susceptibility to E2-induced mammary cancers; and, 2. MCS-X, segregating independently from EMCA-1 suppresses susceptibility to these E2 -induced mammary cancers. Herein they propose to map within the rat genome the locations at which EMCA-1 and MCS-X reside, and confirm the roles of these putative genes as modulators of susceptibility to E2- induced mammary cancers. j They will also define the role of progesterone in the etiology of E2-induced mammary cancer development in the ACI rat strain and further validate this strain as an important animal model for the study of breast cancer.