Pyroptosis is a type of programmed lytic cell death mechanism associated with the activation of inflammasomes and inflammatory caspases, proteolytic cleavage of gasdermin proteins (GSDMA-E and PJVK), resulting in the formation of pores in cellular membranes such as plasma membrane and mitochondrial membranes. Here, I show that GSDMC expression was increased, GSDME (DFNA5) and PJVK (DFNB59) expression were decreased in uterine corpus endometrial carcinoma (UCEC) cells compared to normal endometrial cells. Total percentage of patients affected by mutations in gasdermin family of genes was the highest in UCEC compared to other cancer types. The highest mutation percentage among the members of the protein family was observed for GSDME which also showed the most significant difference in the mRNA expression among other family members between tumor and normal samples, possibly pointing to its relatively higher importance in the pathogenesis of UCEC. Gasdermin family of genes (except GSDMA) had higher transcript levels in serous endometrial adenocarcinoma than in endometrioid endometrial adenocarcinoma, demonstrating the histotype-dependent expression of the most of gasdermin genes in UCEC. Transcript levels of certain gasdermin family members also differed based on residual tumor status and histologic tumor grade; however, the expression of any gasdermin genes did not change depending on menopause status. This study suggests that a better mechanistic understanding of pyroptotic cell death in uterine corpus endometrial carcinoma might help identify novel therapeutic targets for the management of this gynecological malignancy.
Breast cancer is the most common malignancy in women worldwide, with incidence expected to increase by more than 46% by 2040. Breast cancer is classified into various subtypes based on the status of estrogen receptor (ER), progesterone receptor (PR) and HER2 (ERBB2). These subtypes have huge differences in both treatment and prognosis. TNBC (triple-negative breast cancer) is the most lethal among breast cancer subtypes. Pyroptosis is a programmed pro-inflammatory cell death mechanism leading to the formation of membrane pores mediated by gasdermin (GSDM) proteins. I first explored how the transcript levels of gasdermin family of genes (GSDMA-E and PJVK) differ between TNBC and non-TNBC. I found that the expression of GSDMC and GSDME is increased; but, the expression of GSDMD is decreased in TNBC compared with non-TNBC. I further investigated ER-, PR-, and HER2-dependent changes in the expression of GSDMC, GSDMD and GSMDE. I observed decreased GSDMC mRNA expression in breast tumors with ER-positive and PR-positive status than in those with ER-negative and PR-negative status, respectively. In contrast, HER2-positive breast tumors have higher expression of GSDMC compared to HER2-negative breast tumors. Unlike GSDMC, the expression of GSDMD was higher in ER-positive and PR-positive breast cancer samples than in ER-negative and PR-negative samples, respectively. I found that GSDME expression is lower in ER-positive breast tumors compared to ER-negative breast tumors. Lastly, I showed that breast tumors from premenopausal women have slightly higher transcript levels of GSDME than breast tumors from postmenopausal women. Combined, this study points to the possible differences in pyroptotic cell death between TNBC and non-TNBC, and also between different breast cancer subgroups based on receptor status (ER, PR or HER2).