The tumor suppressor PTEN is disrupted in a large proportion of cancers, including in HER2-positive breast cancer, where its loss is associated with resistance to therapy. Upon genotoxic stress, ataxia telangiectasia mutated (ATM) is activated and phosphorylates PTEN on residue 398. To elucidate the physiological role of this molecular event, we generated and analyzed knock-in mice expressing a mutant form of PTEN that cannot be phosphorylated by ATM (PTEN-398A). This mutation accelerated tumorigenesis in a model of HER2-positive breast cancer. Mammary tumors in bi-transgenic mice carrying MMTV-neu and Pten^398A were characterized by DNA damage accumulation but reduced apoptosis. Mechanistically, phosphorylation of PTEN at position 398 is essential for the proper activation of the S phase checkpoint controlled by the PI3K–p27^Kip1–CDK2 axis. Moreover, we linked these defects to the impaired ability of the PTEN-398A protein to relocalize to the plasma membrane in response to genotoxic stress. Altogether, our results uncover a novel role for ATM-dependent PTEN phosphorylation in the control of genomic stability, cell cycle progression, and tumorigenesis.

肿瘤抑制因子 PTEN 在大部分癌症中被破坏，包括 HER2 阳性乳腺癌，其损失与治疗耐药性有关。在遗传毒性应激下，共济失调毛细血管扩张症 (ATM) 被激活并磷酸化残基 398 上的 PTEN。为了阐明这一分子事件的生理作用，我们生成并分析了表达突变形式 PTEN 的敲入小鼠，这种突变形式不能被 ATM 磷酸化（ PTEN-398A）。这种突变加速了 HER2 阳性乳腺癌模型中的肿瘤发生。携带MMTV-neu和Pten ^398A的双转基因小鼠的乳腺肿瘤其特征是 DNA 损伤积累但细胞凋亡减少。从机制上讲，398 位 PTEN 的磷酸化对于正确激活由 PI3K–p27 ^Kip1 –CDK2 轴控制的 S 期检查点至关重要。此外，我们将这些缺陷与 PTEN-398A 蛋白响应基因毒性应激而重新定位到质膜的能力受损联系起来。总之，我们的结果揭示了 ATM 依赖性 PTEN 磷酸化在控制基因组稳定性、细胞周期进程和肿瘤发生中的新作用。