The requirement for cyclin E in c-Myc overexpressing breast cancers

Basal-like triple-negative breast cancers frequently express high levels of c-Myc. This oncoprotein signals to the core cell cycle machinery by impinging on cyclin E. High levels of E-type cyclins (E1 and E2) are often seen in human triple-negative breast tumors. In the current study, we examined the requirement for E-type cyclins in the c-Myc-driven mouse model of breast cancer (MMTV-c-Myc mice). To do so, we crossed cyclin E1- (E1^-/-) and E2- (E2^-/-) deficient mice with MMTV-c-Myc animals, and observed the resulting cyclin E1^-/-/MMTV-c-Myc and cyclin E2^-/-/MMTV-c-Myc females for breast cancer incidence. We found that mice lacking cyclins E1 or E2 developed breast cancers like their cyclin Ewild-type counterparts. In contrast, further reduction of the dosage of E-cyclins in cyclin E1^-/-E2^+/-/MMTV-c-Myc and cyclin E1^+/-E2^-/-/MMTV-c-Myc animals significantly decreased the incidence of mammary carcinomas, revealing arole for E-cyclins in tumor initiation. We also observed that depletion of E-cyclins in human triple-negative breast cancer cell lines halted cell cycle progression, indicating that E-cyclins are essential for tumor cell proliferation. In contrast, we found that the catalytic partner of E-cyclins, the cyclin-dependent kinase 2 (CDK2), is dispensable for the proliferation of these cells. These results indicate that E-cyclins, but not CDK2, play essential and rate-limiting roles in driving the proliferation of c-Myc overexpressing breast cancer cells.

基底样三阴性乳腺癌（basal-like triple-negative breast cancer）通常高表达c-Myc蛋白。该癌蛋白通过靶向作用于E型周期蛋白，向细胞周期核心调控系统传递信号。人类三阴性乳腺肿瘤中常可检测到高表达的E型周期蛋白（E1与E2）。
在本研究中，我们针对c-Myc驱动的乳腺癌小鼠模型（MMTV-c-Myc小鼠），探究了E型周期蛋白的必要性。为此，我们将E1基因敲除（E1^-/-）与E2基因敲除（E2^-/-）小鼠分别与MMTV-c-Myc小鼠进行杂交，对获得的雌性双基因型小鼠cyclin E1^-/-/MMTV-c-Myc及cyclin E2^-/-/MMTV-c-Myc的乳腺癌发病率进行观测。
我们发现，缺失E1或E2型周期蛋白的小鼠，其乳腺癌发病率与野生型E型周期蛋白对照小鼠无显著差异。与之相反，在cyclin E1^-/-E2^+/-/MMTV-c-Myc及cyclin E1^+/-E2^-/-/MMTV-c-Myc小鼠中进一步降低E型周期蛋白的基因拷贝数，可显著降低乳腺腺癌的发病率，揭示了E型周期蛋白在肿瘤起始过程中的作用。
我们同时观测到，在人类三阴性乳腺癌细胞系中敲除E型周期蛋白可阻断细胞周期进程，表明E型周期蛋白对肿瘤细胞增殖至关重要。
与之相反，我们发现E型周期蛋白的催化伴侣——细胞周期蛋白依赖性激酶2（cyclin-dependent kinase 2, CDK2）——对这类细胞的增殖并非必需。
上述结果表明，E型周期蛋白而非CDK2，在驱动c-Myc过表达乳腺癌细胞增殖的过程中发挥了必需且限速的关键作用。