Shull J D, Pennington K L, Reindl T M, Snyder M C, Strecker T E, Spady T J, Tochacek M, McComb R D
Eppley Institute for Research in Cancer and Department of Biochemistry and Molecular Biology , University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Endocrinology. 2001 Dec;142(12):5124-30. doi: 10.1210/endo.142.12.8530.
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.
雌激素与乳腺癌的病因有着千丝万缕的联系。我们已经证明，雌性ACI大鼠在持续接受生理水平的17β-雌二醇（E2）治疗时，表现出独特的患乳腺癌倾向。E2诱导的乳腺癌依赖雌激素，并表现出基因组不稳定。相比之下，遗传相关的哥本哈根（COP）大鼠品系对E2诱导的乳腺癌相对耐药。在本研究中，我们评估了ACI和COP品系之间相互杂交产生的子一代（F(1)）、子二代（F(2)）和回交（BC）后代对E2诱导的乳腺癌的易感性。F(1)后代在E2诱导的乳腺癌发病率方面与亲代ACI品系相似。然而，F(1)群体中的潜伏期显著延长。这些数据表明，在这些杂交中，易感性表现为不完全显性表型。对F(1)、F(2)和BC群体所表现出的表型分析表明，在ACI和COP品系之间的相互杂交中，乳腺癌易感性由一个或两个基因位点修饰。在遗传多样的F(2)和BC群体中，对E2诱导的乳腺癌的易感性与E2诱导的垂体生长无关，这表明对E2诱导的乳腺癌的易感性的遗传基础与E2诱导的催乳素细胞增生的遗传基础不同。
