CENPF Knockdown Inhibits Adriamycin Chemoresistance In Triple Negative Breast Cancer Mediated By Rb-E2F1 Axis

Abstract

Abstract Background: Frequent developed resistance leads to early relapse and short survival in Triple-negative breast cancer (TNBC). Targeting DNA damage response (DDR) has become an effective strategy for overcoming TNBC chemoresistance. CENPF (centromere protein) is a key regulator of cell cycle progression, but its role in TNBC chemotherapy resistance remains unclear. Methods: We Used bioinformatics, immunohistochemical staining and real-time quantitative PCR analysis to explore the expression of CENPF in triple negative breast cancer tissues and cells. Then, we analyze the relationship between CENPF expression with clinicopathological parameters and survival prognosis of patients. The effects of CENPF on the proliferation, apoptosis, cycle, and drug sensitivity of triple negative breast cancer cells were detected in vitro. The chemoresistance mechanisms of CENPF in TNBC cells was evaluated by immunoblotting, immunofluorescence co-localization, and co-immunoprecipitation . Results: Here we found CENPF, highly expressed in TNBC, is associated with poor prognosis in patients receiving chemotherapy. And in vitro CENPF knockdown significantly increased adriamycin (ADR)-induced cytotoxicity in MDA-MB-231 and its ADR-resistant strains (MDA-MB-231/ADR). Then we demonstrated that CENPF targets Chk1-mediated G2/M phase arrest and binds to Rb for competing with E2F1 in TNBC. Collectively Considering crucial role of E2F1 in DNA damage response and DNA repair, a novel mechanism for CENPF to regulate Rb-E2F1 axis will provide new horizons to finally overcome chemotherapy resistance in TNBC. Conclusion: CENPF binds to Rb for competing with E2F1 and promotes Chk1 expression through the Rb/E2F1 axis to enhance chemoresistance to doxorubicin in TNBC.