Transcript levels of cellular senescence marker genes are increased based on high expression of gasdermin family of genes in breast cancer

Abstract

Cellular senescence is a cell state characterized by a generally permanent cell-cycle arrest, generating a broad secretome of inflammatory factors, contributing to pro-inflammatory milieu. Pyroptosis is a highly regulated cell death mechanism with pro-inflammatory characteristics, mediated by gasdermin (GSDM) family of proteins, which has six members: GSDMA-E and PJVK. In the present study, I found that breast tumors with high gasdermin expression have higher expression of senescence marker genes, namely CDKN1A (encoding p21), CDKN2A (encoding p16) and TP53 (encoding p53). This is especially true for high GSDMD- or GSDME-expressing breast tumors, which show higher mRNA levels of three senescence marker genes. This high GSDM-dependent increases in the transcript levels of cellular senescence marker genes is more frequent in breast cancer cells than in non-malignant breast cells, suggesting that the association between gasdermin family of genes and senesence marker genes in terms of expression levels is more strong in the case of tumor. This might point that, in breast cancer, pyroptosis and senescence might be associated; however, whether pyroptosis regulates senescence or vice versa, whether these two processes both reciprocally regulate and control each other, or even whether they share an upstream regulatory pathway remains to be identified. These findings also support previous research demonstrating the promoting effect of pyroptosis on senesence, and that SASP (senescence-associated secretory phenotype) factors can induce GSDMD–dependent pyroptotic cell death in neighboring cells present, in certain contexts. Further mechanistic studies are required to better characterize molecular connections between senescence and pyroptosis in breast cancer.