The pace at which these events occur is dictated by the activity of cyclin-dependent kinases (CDKs), which phosphorylate key substrates to promote DNA synthesis and mitotic progression. Progression through the cell cycle requires the flawless execution of several molecular processes performed in a timely manner to ensure a proficient, and error-free, cell division. PTEN deficiency alter multiple cell cycle checkpoints, possibly leaving less time for DNA damage repair and/or chromosome segregation. However, follow-up work has yielded inconsistent results, suggesting that PTEN regulation of RAD51 at the transcriptional level might be restricted to specific cell-contexts. Further, acting as a co-factor for the transcription factor E2F1, nuclear PTEN appears to regulate the expression of Rad51, a key component of the DNA repair machinery. In the nucleus, PTEN associates with the centromeric binding protein CENP-C and promotes kinetochore assembly and the metaphase-to-anaphase transition. PTEN loss is thought to contribute to genome integrity via at least two molecular mechanisms. Moreover, genetic deletion of PTEN in mouse embryonic fibroblasts (MEFs) causes accumulation of unrepaired DNA double-strand breaks. PTEN loss of function is often associated with genomic instability. The overall response rate reaches approximately 70% when PTEN expression is detected, but only about 20% for patients with negative PTEN expression. Trastuzumab, a monoclonal antibody that binds with high affinity to the extracellular domain of HER2, is an effective therapy in HER2-positive breast cancer patients. Its overexpression, observed in approximately 15–20% of breast cancer cases, is correlated with aggressive clinical behavior and poor prognosis. HER2 is a member of the epidermal growth factor receptor family which possess tyrosine kinase activity. In particular, the expression of PTEN has been proposed to play an important role in human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers. PTEN loss is a frequent event in breast cancer and is closely associated with accelerated progression and poor prognosis. Somatic loss of function mutations of PTEN are found in a variety of human cancers including breast, endometrial carcinoma, glioblastoma multiforme, skin, and prostate cancers. These fundamental cellular processes, when deregulated, can contribute or drive a malignant phenotype. The PI3K pathway regulates diverse cellular processes, including cell metabolism, survival, proliferation, apoptosis, growth, and migration. By dephosphorylating the D3 position of PIP 3, PTEN antagonizes the phosphatidylinositide 3-kinase (PI3K) pathway. PTEN contains an N-terminal phosphatase domain that can dephosphorylate a component of the lipid cellular membrane, phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P 3 or PIP 3). Altogether, our results uncover a novel role for ATM-dependent PTEN phosphorylation in the control of genomic stability, cell cycle progression, and tumorigenesis. 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. 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. Mammary tumors in bi-transgenic mice carrying MMTV-neu and Pten 398A were characterized by DNA damage accumulation but reduced apoptosis. This mutation accelerated tumorigenesis in a model of HER2-positive breast cancer. 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). Upon genotoxic stress, ataxia telangiectasia mutated (ATM) is activated and phosphorylates PTEN on residue 398. ![]() 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.
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