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.
Showing the most recent 10 out of 32 publications
