CDC73 promotes breast cancer through impairing MAPK1 ubiquitination and activating mTOR signaling pathway

Abstract Breast cancer is the most common global malignancy and the leading cause of cancer deaths. CDC73 (Human cell division cycle 73), a nuclear protein, participates transcription regulation and its functions are controversial in malignancies. CDC73 has been reported to be upregulated in breast cancer. The underlying mechanism, however, has not been fully illuminated. In breast cancer, CDC73 could promote the proliferation of tumor cells, and the expression of CDC73 was related to poor prognosis in patients. Here, we found that CBL, an E3 ubiquitin ligase, could interact with CDC73 and promote MAPK1 ubiquitination and degradation of this protein. In addition, silencing MAPK1 led to a suppression of breast cancer cell growth in vitro and in vivo , and even abolished the promoting effects of CDC73 overexpression. We also found that mTOR pathway played a role in CDC73-mediated breast cancer. mTOR pathway inhibitor reversed cell phenotypes induced by CDC73 overexpression. Our study revealed the underlying mechanism of CDC73 in breast cancer: it promoted MAPK1 ubiquitination and degradation so that affected MAPK1 level and subsequently led to tumor progression, providing a novel therapeutic strategy to combat cancer.