STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1

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.

SCAMP3 Regulates EGFR and Promotes Proliferation and Migration of Triple-Negative Breast Cancer Cells through the Modulation of AKT, ERK, and STAT3 Signaling Pathways

“…( Supplementary Table S1 ). The protein encoded by this gene is a member of the STAT family of transcription factors recently identified as a resistance inducer to doxorubicin [ 37 ].…”

Acquired chemoresistance can lead to increased resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus

“… 53 Intriguingly, recent studies show that STAT5A is vital for the development of various cancers and also plays a role in chemoresistance in breast cancer. 53 , 54 STAT6 has been shown to also play a significant role in carcinogenesis and in the early development of colon cancer. 55 , 56 STAT6 function has also been related to cancer cell survival and drug resistance.…”

The long non-coding RNA T cell leukemia homeobox 1 neighbor enhances signal transducer and activator of transcription 5A phosphorylation to promote colon cancer cell invasion, migration, and metastasis

“…To test this possibility directly, we used the STAT5 inhibitor pimozide. Pimozide, which is clinically used to treat schizophrenia, has been reported to inhibit STAT5 phosphorylation in chronic myelogenous leukemia, T-cell prolymphocytic leukemia, osteosarcoma, and breast cancer [ 10 , 30–33 ]. In rescue assays in which HCT116 cells were treated with pimozide, inhibition of STAT5A phosphorylation reversed the enhanced migration and invasion of colon cancer cells following TLX1NB overexpression, suggesting that pimozide has clinical value for treating colon cancer.…”

“…As a member of the signal transducer and activator of transcription (STAT) family, STAT5A is mostly located in the cytoplasm in an inactivated state [ 9 ]. Following stimulation by a series of cytokines, STAT5A is recruited to the Janus kinase/receptor complex and is phosphorylated [ 10 ]. STAT5A then translocates to the nucleus where it functions as a transcription factor [ 11 ].…”