Abstract
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.
Highlights
Chemotherapy currently remains a conventional treatment for breast cancer
In silico analysis suggests epithelial membrane protein 3 (EMP3) as a tumor suppressor in breast cancer To explore whether EMP3 plays a role in breast cancer, the association of EMP3 with the survival of breast cancer patients was analyzed in the TCGA database and Kaplan–Meier plotter website
Higher EMP3 expression was shown to be correlated with longer overall survival (OS), recurrence-free survival (RFS), and distal metastasis-free survival (DMFS) (Fig. 1A, B)
Summary
An increase in DNA damage repair capacity endows cancer cells with insensitivity to DNA-damaging anti-cancer drugs. Homologous recombination repair of DNA double-strand breaks has been demonstrated to be responsible for cancer chemoresistance [1,2,3]. BRCA1 and RAD51 are two key factors involved in homologous recombination repair. Upregulation of BRCA1 and RAD51 impairs the killing effect of DNA-damaging agents on breast cancer cells [4,5,6]. DNA replication is closely associated with DNA damage repair. Homologous recombination is active in the replication phase of the cell cycle [7]. Homologous recombination repair and DNA replication are usually modulated by the same factor or signaling pathway [8,9,10]
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