Journal
FRONTIERS IN ONCOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2021.697950
Keywords
breast cancer; STAT5A; ABCB1; pimozide; doxorubicin resistance
Categories
Funding
- National Natural Science Foundation of China [81672729, 81972597, 81602471, 81972453, 81672840, 82000212]
- Zhejiang Provincial Natural Science Foundation of China [LY19H160059, LY19H160055, LY18H160030, LQ21H160022]
- Zhejiang Provincial Medical and Health Science and Technology Project [2018ZD028, 2021RC003]
- Ningbo Natural Science Foundation [2019A610315]
- Cixi Agricultural and Social Development Science and Technology Project [CN2020006]
- Zheng Shu Medical Elite Scholarship Fund
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This study identified STAT5a as a regulator of ABCB1 expression in breast cancer, acting as a chemoresistance inducer that can be targeted by pimozide. Targeting STAT5a could be a promising strategy for treating chemoresistant breast cancer, and repurposing pimozide for doxorubicin resensitization is attractive due to its safety profile.
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.
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