Estrogens are inextricably linked to the etiology of breast cancer. We have demonstrated that the ACI rat strain exhibits a unique propensity to develop mammary cancer when treated continuously with 17β-estradiol (E2). Treatment of ovary intact ACI rats with E2 results in virtually a 100% incidence of mammary carcinoma with a median latency of approximately 140 days. These mammary cancers are dependent upon exogenous E2 and exhibit genomic instability, a hallmark of breast cancers in humans. In contrast, the Copenhagen (COP) and Brown Norway (BN) rat strains are resistant to E2-induced mammary carcinogenesis. Susceptibility to E2-induced mammary cancer behaves as an incompletely dominant or dominant trait in crosses between the ACI strain and the COP or BN strains. Genetic linkage analyses of several hundred phenotypically defined F2 progeny from reciprocal crosses between the ACI and COP or BN strains revealed a total of seven genetic determinants of susceptibility to E2-induced mammary cancer on chromosomes 2, 3, 4, 5, 6, 7 and 18. The chromosome 5 locus, designated Emca1, determines susceptibility to E2-induced mammary cancer in reciprocal crosses between the highly susceptible ACI strain and the resistant COP or BN strains. Potential candidate genes residing within the Emca1 locus include Cdkn2a, Cdkn2b and Cdkn2c. Studies on Cdkn2a indicate that expression of the p16Ink4a protein product of the Cdkn2a locus is downregulated at an early stage of E2-induced mammary carcinogenesis in the ACI rat. We are currently evaluating these genes further to determine whether and how they contribute to mammary cancer etiology in this model.