TRA2A promoted paclitaxel resistance and tumor progression in triple negative breast cancers via regulating alternative splicing

Treatment of triple-negative breast cancer (TNBC) has been challenging and paclitaxel (PTX) resistance is one of the major obstacles to the better prognosis. Deregulation of alternative splicing (AS) may contribute to tumor progression and chemotherapy resistance. Human AS factor TRA2 has two separate gene paralogs encoding TRA2A and TRA2B proteins. TRA2B is associated with cancer cell survival and therapeutic sensitivity. However the individual role of TRA2A in cancer progression has not been reported. Here we report that TRA2A facilitates proliferation and survival, migration and invasion of TNBC cells. In addition, TRA2A promotes PTX resistance of TNBC by specifically controlling cancer-related splicing, which is independent of other splicing factors. TRA2A overexpression could promote AS of CALU, RSRC2 and PALM during PTX treatment of TNBC cells. The isoform shift of RSRC2 from RSRC2s to RSRC2l leads to a decreased RSRC2 protein expression, which could contribute to TNBC PTX resistance. TRA2A can regulate RSRC2 AS by specifically binding upstream intronic sequence of exon4. Strikingly, TRA2A expression is increased dramatically in TNBC patients, and has close relationship with decreased RSRC2 expression; both of them are associated with poor survival of TNBC. Collectively, our findings suggest that PTX targets the TRA2A-RSRC2 splicing pathway and deregulated TRA2A and RSRC2 expression may confer PTX resistance. In addition to providing a novel molecular mechanism of cancer-related splicing dysregulation, our study demonstrates that expression of TRA2A in conjunction with RSRC2 may provide valuable molecular biomarker evidence for TNBC clinical treatment decisions and patient outcome.

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