Mammary gland stem cells (MaSCs), assumed to be the original cells of breast cancer, play essential roles in regulating mammary gland homeostasis and development. Previously, we identified a crucial regulatory role of TAR DNA-binding protein 43 (TDP-43), an RNA-binding protein, in the progression of triple-negative breast cancer. However, the function of TDP-43 in MaSCs is unclear. Based on single-cell data analysis of the mammary gland, TDP-43 showed potential involvement in the regulation of MaSCs. We therefore investigated the effects of TDP-43 on the mammary gland development. Our data both in vitro and in vivo demonstrated that TDP-43 was required for the mammary gland repopulation, which suggested the potential role in the regulation of MaSCs. Knockdown of TDP-43 inhibited proliferation of mammary epithelial cells (MECs) and mammary morphogenesis. RNA-seq data and other experiments identified that loss of TDP-43 induced the upregulation of genes related to the cell cycle, providing a possible mechanism for TDP-43 in regulating mammary gland repopulation. Thus, our findings indicate a previously unknown role of TDP-43 in MECs.
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