EMP3 negatively modulates breast cancer cell DNA replication, DNA damage repair, and stem-like properties.

Enhanced DNA damage repair capacity attenuates cell killing of DNA-damaging chemotherapeutic agents. In silico analysis showed that epithelial membrane protein 3 (EMP3) is associated with favorable survival, and negatively regulates cell cycle S-phase. Consistently, loss and gain of function studies demonstrated that EMP3 inhibits breast cancer cell S-phage entry, DNA replication, DNA damage repair, and stem-like properties. Moreover, EMP3 blocks Akt-mTOR signaling activation and induces autophagy. EMP3 negatively modulates BRCA1 and RAD51 expression, indicating EMP3 suppresses homologous recombination repair of DNA double-strand breaks. Accordingly, EMP3 sensitizes breast cancer cells to the DNA-damaging drug Adriamycin. EMP3 downregulates YTHDC1, a RNA-binding protein involved in m6a modification, which at least in part mediates the effects of EMP3 on breast cancer cells. Taken together, these data indicate that EMP3 is a putative tumor suppressor in breast cancer, and EMP3 downregulation may be responsible for breast cancer chemoresistance.