ABSTRACT

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.

摘要

基底样三阴性乳腺癌经常表达高水平的 c-Myc。这种癌蛋白通过撞击细胞周期蛋白 E 向核心细胞周期机制发出信号。高水平的 E 型细胞周期蛋白（E1 和 E2）经常出现在人类三阴性乳腺肿瘤中。在当前的研究中，我们检查了 c-Myc 驱动的乳腺癌小鼠模型（MMTV-c-Myc 小鼠）对 E 型细胞周期蛋白的需求。为此，我们将细胞周期蛋白 E1- (E1 ^-/- ) 和 E2- (E2 ^-/- ) 缺陷小鼠与 MMTV-c-Myc 动物交叉，并观察了由此产生的细胞周期蛋白 E1 ^-/- /MMTV-c-Myc 和细胞周期蛋白 E2 ^-/-/MMTV-c-Myc 女性乳腺癌发病率。我们发现缺乏细胞周期蛋白 E1 或 E2 的小鼠会像它们的细胞周期蛋白 Ewild 型小鼠一样患上乳腺癌。相比之下，进一步减少细胞周期蛋白 E1 ^-/- E2 ^+/- /MMTV-c-Myc 和细胞周期蛋白 E1 ^+/- E2 ^-/-中 E-cyclin 的剂量/MMTV-c-Myc 动物显着降低了乳腺癌的发生率，揭示了 E-细胞周期蛋白在肿瘤起始中的作用。我们还观察到人三阴性乳腺癌细胞系中 E-cyclins 的消耗停止了细胞周期进程，表明 E-cyclins 对肿瘤细胞增殖至关重要。相比之下，我们发现 E 细胞周期蛋白的催化伙伴，细胞周期蛋白依赖性激酶 2 (CDK2)，对于这些细胞的增殖是可有可无的。这些结果表明，E-细胞周期蛋白，而不是 CDK2，在驱动 c-Myc 过表达乳腺癌细胞增殖方面发挥着重要的限速作用。