AUTHOR=Li Zhaoqing , Chen Cong , Chen Lini , Hu Dengdi , Yang Xiqian , Zhuo Wenying , Chen Yongxia , Yang Jingjing , Zhou Yulu , Mao Misha , Zhang Xun , Xu Ling , Ju Siwei , Shen Jun , Wang Qinchuan , Dong Minjun , Xie Shuduo , Wei Qun , Jia Yunlu , Zhou Jichun , Wang Linbo TITLE=STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1 JOURNAL=Frontiers in Oncology VOLUME=11 YEAR=2021 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.697950 DOI=10.3389/fonc.2021.697950 ISSN=2234-943X ABSTRACT=

Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in the development of various cancers, but its function in breast cancer is controversial, and its role in chemoresistance in breast cancer remains unexplored. Here we identified STAT5a as a chemoresistance inducer that regulates the expression of ABCB1 in breast cancer and can be targeted by pimozide, an FDA-approved psychotropic drug. First, we found that STAT5a and ABCB1 were expressed at higher levels in doxorubicin-resistant cell lines and chemoresistant patients, and their expression was positively correlated. Then, we confirmed the essential roles of STAT5a and ABCB1 in doxorubicin resistance in breast cancer cells and the regulation of ABCB1 transcription by STAT5a. Subsequently, the efficacy of pimozide in inhibiting STAT5a and sensitizing doxorubicin-resistant breast cancer cells was tested. Finally, we verified the role of STAT5a in doxorubicin resistance in breast cancer and the efficacy of pimozide in reversing this resistance in vivo. Our study demonstrated the vital role of STAT5a in doxorubicin resistance in breast cancer. Targeting STAT5a might be a promising strategy for treating doxorubicin-resistant breast cancer. Moreover, repurposing pimozide for doxorubicin resensitization is attractive due to the safety profile of pimozide.