Role of Gasdermin E mediated pyroptosis in the response of different breast cancer molecular subtypes to chemo- and Immunotherapy

Breast cancer (BC) is the most prevalent cancer subtype worldwide, and the number of new cases is expected to rise dramatically in the coming years. Since BC is a heterogenous disease, its systemic treatment has shown a variation in the response of patients, which requires a deeper understanding of cancer cell biology and its interplay with its microenvironment. Gasdermin E (GSDME) is a member of gasdermin family of proteins that induce pyroptosis which is a form of regulated necrosis.This form of cell death is more effective than other modes of cell death as it can activate tumor immunity by exposing tumor-specific antigens to the immune cells. GSDME was found to be downregulated in cancer tissue in comparison with the surrounding normal cells, this is attributed to promoter hyper-methylation. It is also affected by a multiple loss-of-function supporting the consideration of GSDME as a tumor suppressor gene. GSDME expression was previously reported to be negatively regulated by oestrogen receptor (ER) levels in hormone-positive breast cancer. However, the exact mechanism by which ER infers down-regulation of GSDME is not yet known. Also, few other studies done on publicly available patient data suggests a role of the progesterone receptor (PR) and the epidermal growth factor receptor 2 (HER2) in controlling GSDME levels. The current work aims to investigate the mechanism the crosstalk between the hormone receptors, HER2 and GSDME expression and activity. Understanding their regulatory roles might provide an insight to re-establish GSDME expression in breast cancer cells using hormone antagonists and HER2 targeted therapy, which can sensitize BC cells to chemotherapy and immune checkpoint inhibitors.