Department of Experimental Radiation Oncology, University of Texas, MD Anderson Cancer Center, TX, USA.
Cancer Res. 2011 May 1;71(9):3377-86. doi: 10.1158/0008-5472.CAN-10-4086. Epub 2011 Mar 8.
Cyclin E activates Cdk2, controls centrosome duplication, and regulates histone gene transcription. Cyclin E is deregulated in cancer and appears as low-molecular-weight (LMW) isoforms that correlate strongly with decreased survival in breast cancer patients. Transgenic mice overexpressing LMW-cyclin E have increased incidence of mammary tumors and distant metastasis when compared with mice that had full-length cyclin E. To specifically test the requirement for Cdk2 in LMW-cyclin E-mediated mammary tumorigenesis, we generated transgenic mice, which expressed LMW-cyclin E in a Cdk2-deficient background. We found that mammary gland development proceeds relatively normally in these animals, indicating that Cdk2 kinase activity is largely dispensable for this process. However, Cdk2-deficient mice were completely resistant to LMW-cyclin E-mediated mammary tumors. Cdk2 wild-type or heterozygous mice succumbed to mammary tumors with mean latencies of 16 and 19.5 months, respectively, but Cdk2 nullizygous littermates did not display tumors through 24 months. Similarly, continuous administration of two different Cdk inhibitors significantly delayed LMW-cyclin E-induced mammary tumor progression. Triple transgenic mice generated in a p53 heterozygous background also displayed no tumors. Finally, we found that Cdk2 silencing induced cell death in LMW-overexpressing breast cancer cell lines, but not in cell lines lacking LMW expression. Our findings establish a requirement for Cdk2 in LMW-cyclin E-mediated mammary tumorigenesis, arguing that human breast tumors overexpressing LMW-cyclin E are prime candidates for anti-Cdk2 therapy.
细胞周期蛋白 E 激活 CDK2，控制中心体复制，并调节组蛋白基因转录。细胞周期蛋白 E 在癌症中失调，表现为低分子量（LMW）同工型，与乳腺癌患者的生存率降低密切相关。与表达全长细胞周期蛋白 E 的小鼠相比，过度表达 LMW-细胞周期蛋白 E 的转基因小鼠具有更高的乳腺肿瘤发生率和远处转移率。为了专门测试 CDK2 在 LMW-细胞周期蛋白 E 介导的乳腺肿瘤发生中的需求，我们生成了转基因小鼠，其在 CDK2 缺陷背景下表达 LMW-细胞周期蛋白 E。我们发现这些动物的乳腺发育相对正常，表明 CDK2 激酶活性在很大程度上是不必要的。然而，Cdk2 缺陷型小鼠对 LMW-细胞周期蛋白 E 介导的乳腺肿瘤完全具有抗性。Cdk2 野生型或杂合型小鼠分别在 16 个月和 19.5 个月时屈服于乳腺肿瘤，但 Cdk2 纯合缺失型同窝仔鼠在 24 个月时未显示肿瘤。同样，两种不同的 CDK 抑制剂的连续给药显著延迟了 LMW-细胞周期蛋白 E 诱导的乳腺肿瘤进展。在 p53 杂合背景下生成的三重转基因小鼠也未显示肿瘤。最后，我们发现 Cdk2 沉默诱导 LMW 过表达的乳腺癌细胞系中的细胞死亡，但在缺乏 LMW 表达的细胞系中则没有。我们的发现确立了 CDK2 在 LMW-细胞周期蛋白 E 介导的乳腺肿瘤发生中的需求，表明过度表达 LMW-细胞周期蛋白 E 的人类乳腺癌肿瘤是抗 CDK2 治疗的主要候选者。
