Resistance to chemotherapy remains a major obstacle to the successful treatment of breast cancer. More than 80% of patients who receive neoadjuvant chemotherapy (NAC) do not achieve a pathological complete response. In this study, we report a novel p62 mRNA isoform with a short 3′-UTR (p62-SU, 662-nt) that is associated with chemoresistance in breast cancer cells and tissue specimens. The p62 mRNA isoform was identified by RNA sequencing with qRT-PCR, 3′-RACE, and northern blot analysis. In vitro and in vivo, ectopic expression of p62-SU promoted breast cancer cell proliferation, migration, invasion, and chemoresistance compared with the p62 mRNA isoform with a full-length 3′-UTR (p62-LU, 1,485-nt). Mechanistically, CPSF1 modulated the 3′-UTR of p62 through alternative polyadenylation. In addition, p62-SU escaped miR-124-3p-mediated repression and upregulated p62-SU protein expression, thereby inducing p62-dependent chemoresistance. These data suggest that a CPSF1-p62-miR-124-3p signaling axis is responsible for reduced sensitivity of breast cancer to chemotherapy.
<div>Abstract<p>Resistance to chemotherapy remains a major obstacle to the successful treatment of breast cancer. More than 80% of patients who receive neoadjuvant chemotherapy (NAC) do not achieve a pathologic complete response. In this study, we report a novel p62 mRNA isoform with a short 3′-UTR (untranslated region; p62-SU, 662-nt) that is associated with chemoresistance in breast cancer cells and tissue specimens. The p62 mRNA isoform was identified by RNA sequencing with qRT-PCR, 3′-RACE, and Northern blot analysis. <i>In vitro</i> and <i>in vivo</i>, ectopic expression of p62-SU promoted breast cancer cell proliferation, migration, invasion, and chemoresistance compared with the p62 mRNA isoform with a full-length 3′-UTR (p62-LU, 1,485-nt). Mechanistically, cleavage and polyadenylation specific factor 1 (CPSF1) modulated the 3′-UTR of p62 through alternative polyadenylation. In addition, p62-SU escaped miR-124-3p–mediated repression and upregulated p62-SU protein expression, thereby inducing p62-dependent chemoresistance. These data suggest that a CPSF1-p62-miR-124-3p signaling axis is responsible for reduced sensitivity of breast cancer to chemotherapy.</p>Significance:<p>Resistance to NAC in breast cancer is driven by a novel p62 mRNA isoform that escapes miRNA-mediated repression and leads to increased p62 protein expression.</p></div>
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