Reddy Haritha K D L, Mettus Richard V, Rane Sushil G, Graña Xavier, Litvin Judith, Reddy E Premkumar
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Cancer Res. 2005 Nov 15;65(22):10174-8. doi: 10.1158/0008-5472.CAN-05-2639.
Previous work has shown that cyclin D1 expression is required for neu- and ras-induced, but not wnt- or c-myc-induced, breast tumorigenesis in mice. Although cyclin D1 binds and activates cyclin-dependent kinase 4 (Cdk4), thereby mediating activation of a program of E2F-dependent gene expression, it has been suggested that the oncogenic activities of cyclin D1 are independent of Cdk4. To determine whether Cdk4 expression is required for breast tumorigenesis in mice, we have generated compound mice ectopically expressing the neu or wnt oncogenes in the mammary glands of wild-type and Cdk4-/- mice. Our results show that Cdk4 expression is required for efficient neu-induced tumorigenesis but is dispensable for wnt-induced breast tumorigenesis. In contrast to results previously observed in the mammary glands of cyclin D1-/- virgin females, our results show defects in mammary gland development in Cdk4-/- virgin females, suggesting differences in compensatory mechanisms in the absence of either subunit of the cyclin D1/Cdk4 complex. These results suggest that drugs targeted to inhibit Cdk4 activities could be developed to specifically treat certain breast tumors as Cdk4 is not essential for viability.
先前的研究表明，细胞周期蛋白D1的表达是neu和ras诱导的小鼠乳腺肿瘤发生所必需的，但不是wnt或c-myc诱导的乳腺肿瘤发生所必需的。虽然细胞周期蛋白D1结合并激活细胞周期蛋白依赖性激酶4（Cdk4），从而介导E2F依赖性基因表达程序的激活，但有人提出细胞周期蛋白D1的致癌活性独立于Cdk4。为了确定Cdk4的表达是否是小鼠乳腺肿瘤发生所必需的，我们构建了在野生型和Cdk4基因敲除小鼠的乳腺中异位表达neu或wnt癌基因的复合小鼠。我们的结果表明，Cdk4的表达是有效的neu诱导的肿瘤发生所必需的，但对于wnt诱导的乳腺肿瘤发生是可有可无的。与先前在细胞周期蛋白D1基因敲除处女雌鼠乳腺中观察到的结果相反，我们的结果显示Cdk4基因敲除处女雌鼠的乳腺发育存在缺陷，这表明在细胞周期蛋白D1/Cdk4复合物任一亚基缺失时，补偿机制存在差异。这些结果表明，由于Cdk4对生存力不是必需的，可以开发靶向抑制Cdk4活性的药物来特异性治疗某些乳腺肿瘤。
