Molecular Pharmacology & Biological Chemistry, Northwestern University, Chicago, IL 60611, USA.
Neoplasia. 2011 May;13(5):439-44. doi: 10.1593/neo.101704.
The concept of targeting G(1) cyclin-dependent kinases (CDKs) in breast cancer treatments is supported by the fact that the genetic ablation of Cdk4 had minimal impacts on normal cell proliferation in majority of cell types, resulting in near-normal mouse development, whereas such loss of Cdk4 completely abrogated ErbB-2/neu-induced mammary tumorigenesis in mice. In most human breast cancer tissues, another G(1)-regulatory CDK, CDK2, is also hyperactivated by various mechanisms and is believed to be an important therapeutic target. In this report, we provide genetic evidence that CDK2 is essential for proliferation and oncogenesis of murine mammary epithelial cells. We observed that 87% of Cdk2-null mice were protected from ErbB-2-induced mammary tumorigenesis. Mouse embryonic fibroblasts isolated from Cdk2-null mouse showed resistance to various oncogene-induced transformation. Previously, we have reported that hemizygous loss of Cdc25A, the major activator of CDK2, can also protect mice from ErbB-2-induced mammary tumorigenesis [Cancer Res (2007) 67(14): 6605-11]. Thus, we propose that CDC25A-CDK2 pathway is critical for the oncogenic action of ErbB-2 in mammary epithelial cells, in a manner similar to Cyclin D1/CDK4 pathway.
针对乳腺癌治疗中 G(1) 细胞周期蛋白依赖性激酶 (CDK) 的靶向治疗概念得到了以下事实的支持：在大多数细胞类型中，Cdk4 的基因缺失对正常细胞增殖的影响极小，导致小鼠发育基本正常，而 Cdk4 的这种缺失完全消除了 ErbB-2/neu 诱导的小鼠乳腺肿瘤发生。在大多数人类乳腺癌组织中，另一种 G(1) 调节 CDK，即 CDK2，也通过各种机制被过度激活，被认为是一个重要的治疗靶点。在本报告中，我们提供了遗传证据，证明 CDK2 是小鼠乳腺上皮细胞增殖和致癌所必需的。我们观察到，87%的 Cdk2 缺失小鼠免受 ErbB-2 诱导的乳腺肿瘤发生的保护。从 Cdk2 缺失小鼠分离的小鼠胚胎成纤维细胞对各种致癌基因诱导的转化具有抗性。先前，我们已经报道过 Cdc25A（CDK2 的主要激活剂）的杂合缺失也可以保护小鼠免受 ErbB-2 诱导的乳腺肿瘤发生[Cancer Res（2007）67（14）：6605-11]。因此，我们提出 CDC25A-CDK2 通路对于 ErbB-2 在乳腺上皮细胞中的致癌作用至关重要，其方式类似于 Cyclin D1/CDK4 通路。
