Characterization of GSDMD as a Positive Regulator of Breast Cancer Cell Proliferation and Mammary Tumorigenesis

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Zhang, Derek
Breast cancer , GSDMD , Gasdermins , GLUT1 , Cell energy metabolism
Breast cancer (BC) is the most frequently diagnosed cancer and is classified into subtypes based on the presence or absence of hormone receptors. These molecular markers can be exploited for targeted therapy, which has led to substantial improvements in BC prognosis and survival rates. Yet, three key challenges persist. First, BC without any receptors, called triple-negative BC, is limited in effective treatment options. Secondly, the prevalence of drug resistance is high across all subtypes. Lastly, BC metastasis is presently incurable and the main cause of BC-related death. The gasdermins (GSDMs) are a newly characterized gene family expressed in a wide array of human tissues and regulate many cellular roles, namely cell proliferation and cell death. The GSDMs are most famous for inducing a pro-inflammatory, lytic form of programmed cell death, known as pyroptosis. Recently, GSDM dysregulation has been implicated in a variety of cancers. Interestingly, GSDMD, the most well-characterized member, has been reportedly overexpressed in BC. However, its role in tumorigenesis and underlying molecular mechanisms are unknown. In this study, we ascertained the protein and mRNA expression levels of GSDMD in BC and characterized its oncogenic role in cell proliferation and anchorage-independent cell growth. Through a proteomic screen, we then discovered a bona fide function of GSDMD as a regulator of cell energy metabolism in BC tumorigenesis. We further investigated the protein-protein interaction between GSDMD and glucose transporter 1 (GLUT1), a protein pivotal in glucose uptake and metabolism. Here, we revealed that GSDMD and GLUT1’s interaction synergistically enhanced glucose transport activity and cell proliferation in BC cells. Future elucidation of these findings using in vivo models will validate GSDMD’s pro-cancer role in BC and contribute significantly to the holistic understanding of GSDMD in cancer development.
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