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.
Fig: In silico analysis suggests EMP3 as a tumor suppressor in breast cancer: A The association of EMP3 with OS was analyzed in the TCGA database. B The association of EMP3 with OS, RFS, and DMFS was analyzed in Kaplan–Meier plotter website. C A heat map was generated from the CCLE database demonstrating the correlation of EMP3 with factors related to the S-phase. D Go analysis of the gene pathways differentially expressed between EMP3-high and EMP3-low breast cancer samples in the TCGA database was performed. Four representative GSEA-enrichment plots were shown.
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.
Zhou, K., Sun, Y., Dong, D. et al. EMP3 negatively modulates breast cancer cell DNA replication, DNA damage repair, and stem-like properties. Cell Death Dis 12, 844 (2021). https://doi.org/10.1038/s41419-021-04140-6