Estrogens have been inextricably linked to the etiology of breast cancer. We have demonstrated that the female ACI rat exhibits a unique propensity to develop mammary cancers when treated continuously with physiological levels of 17 beta-estradiol (E2). The E2-induced mammary cancers are estrogen dependent and exhibit genomic instability. In contrast, the genetically related Copenhagen (COP) rat strain is relatively resistant to E2-induced mammary cancers. In this study we evaluated susceptibility to E2-induced mammary cancers in first filial (F(1)), second filial (F(2)), and backcross (BC) progeny generated from reciprocal intercrosses between the ACI and COP strains. F(1) progeny resembled the parental ACI strain with respect to incidence of E2-induced mammary cancers. However, latency was significantly prolonged in the F(1) populations. These data indicate that susceptibility behaves as an incompletely dominant phenotype in these crosses. Analysis of phenotypes exhibited by the F(1), F(2), and BC populations suggests that mammary cancer susceptibility is modified by one or two genetic loci in the reciprocal intercrosses between the ACI and COP strains. Susceptibility to E2-induced mammary cancers did not correlate with E2-induced pituitary growth in the genetically diverse F(2) and BC populations, suggesting that the genetic bases for susceptibility to E2-induced mammary cancers differ from those for E2-induced lactotroph hyperplasia.