Estrogen /progesterone receptor-gasdermin E axis links hormone signalling to pyroptotic cell death, anti-tumour immunity and response to chemotherapy in breast cancer cells

Hormone receptor signalling orchestrates different pathways in breast cancer (BC). Gasdermin E (GSDME), a key pyroptosis-inducing protein, has emerged as an important modulator of immunogenic cell death and anti-tumor immunity. We aim to investigate the regulatory and functional implications of the relationship between hormone receptors and GSDME expression in BC. The impact of hormone receptor inhibition/downregulation on GSDME level and activity was studied by immunofluorescence and lactate dehydrogenase release assay. The potential regulatory role of hormone receptors was tested by polymerase chain reaction, chromatin immunoprecipitation and dual luciferase reporter assay, while the influence of GSDME on the sensitivity of BC cell lines to doxorubicin was studied by sulforhodamine B. The impact of GSDME on cytotoxic immune cells was studied in patient samples. A mass spectroscopic analysis was done to define the pathways affected by GSDME downregulation. Our findings herein demonstrate for the first time that estrogen and progesterone receptors act as transcription repressors of GSDME in hormone receptor-positive BC cells. Pharmacological/biological inhibition of hormone receptors, led to a significant upregulation of GSDME, which facilitated its cleavage, membrane translocation of its N-terminal fragment and subsequent induction of pyroptosis. These events were accompanied by enhanced immune cell activation, including increased natural killer (NK) cell cytotoxicity and a favourable T cell infiltration. Collectively, our findings uncover a novel ER/PR-GSDME regulatory axis linking hormone receptor signalling to pyroptosis, chemosensitivity, and components of anti-tumor immunity in BC. This work highlights GSDME as a predictive biomarker for combination therapies involving hormone receptor inhibitors, chemotherapy, and immune checkpoint inhibitors (ICIs) in BC.