HGF/c‐Met Promotes Breast Cancer Tamoxifen Resistance Through the EZH2/HOTAIR‐miR‐141/200a Feedback Signaling Pathway

ABSTRACT Tamoxifen is one of the most frequently used endocrine medications for the treatment of estrogen receptor‐positive (ER + ) breast cancer (BC). Unfortunately, tamoxifen resistance (TR) brings more challenges to the clinical treatment, and the mechanisms of TR have not yet been fully clarified. HGF/c‐Met is closely associated with cancer metastasis, but whether it is involved in TR remains unclear. In our study, we found that the activation of HGF/c‐Met was crucial for TR maintenance. Synergistic interaction with HOTAIR and EZH2 accelerated HGF expression by repressing miR‐141/200a. Additionally, HGF/c‐Met activated NF‐κB, forming a positive feedback loop of EZH2/HOTAIR‐miR‐141/200a‐HGF/c‐Met‐NF‐κB. Our findings indicated that HGF/c‐Met functioned as an important biomarker for TR, and HGF/c‐Met inhibition provided a novel approach to TR treatment.