Abstract
Chemoresistance is a major obstacle to effective breast cancer chemotherapy. However, the underlying molecular mechanisms remain unclear. In this study, nuclear receptor coactivator 3 (NCOA3) was found to be significantly increased in taxol-resistant breast cancer tissues and cells. Moreover, overexpression of NCOA3 enhanced breast cancer cell resistance to taxol, whereas depletion of NCOA3 decreased taxol resistance. Subsequently, we investigated whether NCOA3 expression was regulated by miRNAs in breast cancer. By bioinformatics prediction in combination with the data of previous report, miR-17 and miR-20b were selected as the potential miRNAs targeting NCOA3. By real-time PCR analysis, we found that miR-17 and miR-20b were significantly reduced in taxol-resistant breast cancer tissues and cells. In addition, we provided some experimental evidences that miR-17 and miR-20b attenuated breast cancer resistance to taxol in vitro and in vivo models. Furthermore, by luciferase reporter assays, we further validated that both miR-17 and miR-20b directly binded the 3′-untranslated region of NCOA3 mRNA and inhibited its expression in breast cancer cells. Finally, both miR-17 and miR-20b levels were found to be significantly negatively correlated with NCOA3 mRNA levels in breast cancer tissues. Together, our results indicated that loss of miR-17 and miR-20b enhanced breast cancer resistance to taxol by upregulating NCOA3 levels. Our study suggested miR-17, miR-20b and NCOA3 may serve as some predictive biomarkers and potential therapeutic targets in taxol-resistant breast cancer treatment.
Highlights
Taxol as an important chemotherapeutic agent in the treatment of breast cancer have shown promise, cancer cells resistance to taxol frequently results in the subsequent recurrence of cancer.[1]
To assess whether Nuclear receptor coactivator 3 (NCOA3) has a role in breast cancer resistance to taxol, real-time PCR (RT-PCR) was used to analyze NCOA3 expression in breast carcinoma specimens
We verified that NCOA3 was upregulated in taxol-resistant MCF-7 and 231 breast cancer
Summary
Taxol (paclitaxel) as an important chemotherapeutic agent in the treatment of breast cancer have shown promise, cancer cells resistance to taxol frequently results in the subsequent recurrence of cancer.[1]. NCOA3 enhances the activity of a number of other transcription factors, such as E2F-1, AP-1, NF-κB and STAT6.7 NCOA3 has been found to have important role in a number of biological processes, such as cell proliferation, apoptosis and migration.[8,9] NCOA3 gene amplification has been found in 2–10% of human breast cancer.[10] NCOA3 is overexpressed in 30–60% breast cancer and associated with high histological grade, advanced stage and poor prognosis.[10].
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