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Genetic Bases of Estrogen-Induced Tumorigenesis in the Rat: Mapping of Loci Controlling Susceptibility to Mammary Cancer in a Brown Norway x ACI Intercross

¹ Eppley Institute for Research in Cancer; Departments of ² Genetics, Cell Biology, and Anatomy; ³ Biochemistry and Molecular Biology; ⁴ Preventive and Societal Medicine; and ⁵ Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska

Requests for reprints: James D. Shull, Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, 6005 Durham Research Center, 985805 Nebraska Medical Center, Omaha, NE 68198-5805. Phone: 402-559-4633; Fax: 402-559-7328; E-mail: jshull{at}unmc.edu.

Exposure to estrogens is associated with an increased risk of breast cancer. Our laboratory has shown that the ACI rat is uniquely susceptible to 17ß-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)F₂ 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. (Cancer Res 2006; 66(15): 7793-800)

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