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.
Highlights
Breast cancer is the most common malignant tumor in women
Signal transducer and activator of transcription (STAT) 5a belongs to the STAT family, which consists of seven members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6) and participates in essential biological behaviors in cells
Data mining based on GSE87455 was conducted to explore whether STAT5a is involved in chemoresistance in breast cancer [23]
Summary
Breast cancer is the most common malignant tumor in women. Every year, 1.7 million people are diagnosed worldwide, and approximately half a million people die from this disease [1]. Chemoresistance is a main cause of breast cancer-related death, as it results in recurrence and metastasis. Overcoming this issue is critical to improving the prognosis of patients with breast cancer. Stat5a and stat5b derived from distinct but chromosome-linked genes that map to chromosome 17 (bands q11-1 to q22) [4]. These two proteins share 94% identity in their amino acid sequences, with the greatest difference in the C-terminal phosphotyrosyl tail and transactivation domain [5]. DNA-damaging agents such as doxorubicin are reported to induce STAT5a expression in breast cancer [16]; the exact role of STAT5a in chemoresistance in breast cancer remains unknown
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