HSC70 Promotes Breast Cancer Progression via PTEN Autophagic Degradation and PI3K/AKT/mTOR Activation

ABSTRACT Heat shock cognate protein 70 (HSC70) functions as a molecular chaperone and plays a crucial role in the regulation of intracellular protein modifications that are involved in tumor autophagy. However, its expression and mechanism in breast cancer have not been studied. The expression of HSC70 was verified by TCGA database and breast cancer patient tissue. We established breast cancer cell models and mouse models using knockdown HSC70. The expression and mechanism of HSC70 in breast cancer were investigated by immunocoprecipitation, protein stability, RNA stability, flow cytometry and biogenic analysis. In this study, we found that HSC70 is highly expressed in breast cancer and that high HSC70 expression positive correlated with poor prognosis using TCGA database and patient tissue verification. Subsequent experimental verification demonstrated that HSC70 drives cell cycle progression and promotes proliferation in breast cancer. Further studies revealed that HSC70 significantly promoted the phosphorylation of PI3K, AKT and mTOR but did not affect the total protein levels. Additionally, the AKT agonist SC79 reversed the effects of HSC70 knockdown on proliferation and cell cycle progression of breast cancer cells. Mechanistically, HSC70 reduces the protein stability of PTEN but does not change its mRNA level, suggesting that HSC70 binds to PTEN and promotes its autophagic degradation. More importantly, in vivo experiments demonstrated that HSC70 knockdown results in slower tumor proliferation and growth. In conclusion, HSC70 can bind to PTEN and promote its autophagic degradation, thereby activating the PI3K/AKT/mTOR signaling pathway to promote cell cycle progression and proliferation in breast cancer. These findings suggest that HSC70 may be a feasible target for breast cancer treatment.