Lapointe J, Labrie C
Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Laval University, Québec, Canada G1V 4G2.
Endocrinology. 2001 Oct;142(10):4331-8. doi: 10.1210/endo.142.10.8417.
Androgens are known to inhibit the growth of breast cancer cells, but the molecular mechanism of androgen-induced growth inhibition remains unknown. To address this question, we examined functional and quantitative alterations in cell cycle regulators in the E-responsive CAMA-1 breast cancer cell line. We report here that the androgen 5 alpha-dihydrotestosterone inhibits the proliferation of CAMA-1 breast cancer cells. This inhibition of cell proliferation was dose dependent, and maximal inhibition of E2-stimulated proliferation was observed at the concentration of 1 nM 5 alpha-dihydrotestosterone. 5 alpha-Dihydrotestosterone-induced growth arrest was accompanied by an increase in the proportion of cells in the G(1) phase of the cell cycle. Compared with control cells, 5 alpha-dihydrotestosterone-treated cells showed an increase in the relative proportion of hypophosphorylated retinoblastoma protein consistent with G(1) arrest. In CAMA-1 cells, 5 alpha-dihydrotestosterone caused an accumulation of the cyclin-dependent kinase inhibitor p27(Kip1). Cyclin E-cyclin-dependent kinase-2-associated kinase activity was strongly inhibited in 5 alpha-dihydrotestosterone-treated cells, and immunoprecipitation-Western blot analysis showed an increase in the amount of p27(Kip1) associated with cyclin E-cyclin-dependent kinase-2 complexes. These results suggest that inhibition of breast cancer cell growth by androgens may be mediated at least in part by inactivation of the cyclin E-cyclin-dependent kinase-2 complexes by p27(Kip1).
已知雄激素可抑制乳腺癌细胞的生长，但雄激素诱导生长抑制的分子机制仍不清楚。为了解决这个问题，我们检测了雌激素反应性CAMA-1乳腺癌细胞系中细胞周期调节因子的功能和定量变化。我们在此报告，雄激素5α-双氢睾酮可抑制CAMA-1乳腺癌细胞的增殖。这种对细胞增殖的抑制呈剂量依赖性，在1 nM 5α-双氢睾酮浓度下观察到对雌激素刺激的增殖的最大抑制。5α-双氢睾酮诱导的生长停滞伴随着细胞周期G(1)期细胞比例的增加。与对照细胞相比，经5α-双氢睾酮处理的细胞中低磷酸化视网膜母细胞瘤蛋白的相对比例增加，这与G(1)期停滞一致。在CAMA-1细胞中，5α-双氢睾酮导致细胞周期蛋白依赖性激酶抑制剂p27(Kip1)的积累。在经5α-双氢睾酮处理的细胞中，细胞周期蛋白E-细胞周期蛋白依赖性激酶-2相关激酶活性受到强烈抑制，免疫沉淀-蛋白质印迹分析显示与细胞周期蛋白E-细胞周期蛋白依赖性激酶-2复合物相关的p27(Kip1)量增加。这些结果表明，雄激素对乳腺癌细胞生长的抑制可能至少部分是由p27(Kip1)使细胞周期蛋白E-细胞周期蛋白依赖性激酶-2复合物失活介导的。
