TDP-43 is Required for Mammary Gland Repopulation and Proliferation of Mammary Epithelial Cells

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.