ZEB1 Confers Chemotherapeutic Resistance To Breast Cancer By Activating ATM

Chemotherapy is a major part of comprehensive treatment for breast cancer, however, chemoresistance also leads to the failure of the treatment of breast cancer, becomes one of the main obstacles for breast cancer treatment. Thus, to investigate the molecular mechanism of breast cancer chemoresistance and investigate new treatment strategies are the key tasks for the current studies.Although zinc finger E-box binding homeobox 1(ZEB1) has been identified as a key factor in the regulation of breast cancer differentiation and metastasis, its potential role in modulating tumor chemoresistance has not been fully understood. Here, we examined ZEB1 expression in 233 subjects with human breast cancer after they received anthracycline-based neoadjuvant chemotherapy. Patients with tumors that expressed high levels of ZEB1 responded poorly to the treatment. Next, ZEB1 was overexpressed or knocked down in breast cancer cells and then treated with genotoxic drugs, such as epirubicin(EPI). ZEB1 overexpression reduced EPI-induced cell growth inhibition and production of γH2AX, a marker for DNA damage response(DDR), whereas ZEB1 knockdown had the opposite effect. To further assess the mechanistic cause of ZEB1-regulated breast cancer chemoresistance, we first performed chromatin immunoprecipitation(ChIP) coupled deep DNA sequencing(ChIP-seq) to identify endogenous transcriptional targets of ZEB1 in MDA-MB-231 cells, after deeply analysis of these target genes, we finally confirmed ataxia-telangiectasia mutation(ATM) kinase act as a target gene for ZEB1. We then designed a series of truncated and mutated ATM promoter-reporter constructs for analysis, and the results suggested that ZEB1 activates ATM transcription. In response to EPI treatment, ZEB1 transcriptionally activated the expression of ATM by forming a ZEB1/p300/PCAF complex on its promoter, leading to increased homologous recombination(HR)-mediated DNA damage repair and the clearance of DNA breaks. Thus, inhibition of ATM activity attenuated the effect of ZEB1 on cell growth inhibition and γH2AX production and thus restored cell sensitivity to EPI treatment. Using a nude mouse xenograft model, we confirmed that ZEB1 overexpression decreased breast cancer responsiveness to EPI treatment in vivo. Collectively, our findings suggest that ZEB1 is a crucial determinant of chemotherapeutic resistance in breast cancer.