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The hotspot mutation H1047R in the oncogenic PIK3CA gene is frequently detected in breast cancer and enhances the enzymatic activity of PI3K to activate AKT/mTOR signaling cascade. Aberrant elevated PI3K activation has been reported to promote the tumorigenesis of breast cancer, but the mechanisms underlying are still needed to be elucidated. Here, we found that continuously activating PIK3CAH1047R conferred human mammary epithelial MCF‐10A cells to cellular senescence upon serum‐starvation. Similarly, breast cancer T47D and HCC1954 cells harboring H1047R mutation were senescent when cells were deprived of serum. PI3K/AKT/mTOR axis but not p53 or RB might be required for the induction of senescence. Notably, membrane metallo‐endopeptidase (MME) was identified as a downstream effector of PI3K to mediate the induction of senescence, which might be associated with its glycosylation. Senescent cells elicited a distinct secretome dependent on PI3K and MME. Specifically, IL‐6 promoted the proliferation of normal cells and CCL2 induced the M2‐like polarization of macrophages, which might create an immunosuppressive microenvironment during the initiation and/or development of breast cancer. This study shed new light on the tumorigenesis induced by hyper‐activated PI3K and might provide new clues for the prevention and therapy of breast cancer.

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Phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma (ESCC). It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kα inhibitors in an aim to improve the clinical responsive rate in ESCC. Here, ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33, a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC. Elevated level of cyclin D1, p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells. CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase, which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2. Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1, which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21. Moreover, CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33. These findings provided mechanistic rationale to evaluate PI3Kα inhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.