title: BRCA1/p220 loss triggers BRCA1-IRIS overexpression via mRNA stabilization in breast cancer cells.
abstract: BRCA1/p220-assocaited and triple negative/basal-like (TN/BL) tumors are aggressive and incurable breast cancer diseases that share among other features the no/low BRCA1/p220 expression. Here we show that BRCA1/p220 silencing in normal human mammary epithelial (HME) cells reduces expression of two RNA-destabilizing proteins, namely AUF1 and pCBP2, both proteins bind and destabilize BRCA1-IRIS mRNA. BRCA1-IRIS overexpression in HME cells triggers expression of several TN/BL markers, e.g., cytokeratins 5 and 17, p-cadherin, EGFR and cyclin E as well as expression and activation of the pro-survival proteins; AKT and survivin. BRCA1-IRIS silencing in the TN/BL cell line, SUM149 or restoration of BRCA1/p220 expression in the mutant cell line, HCC1937 reduced expression of TN/BL markers, AKT and survivin and induced cell death. Collectively, we propose that BRCA1/p220 loss of expression or function triggers BRCA1-IRIS overexpression through a post-transcriptional mechanism, which in turn promotes formation of aggressive and invasive breast tumors by inducing expression of TN/BL and survival proteins.
authors.affiliation: Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Nicole
authors.initials: N
authors.lastname: Mullins
authors.forename: Zannel
authors.initials: Z
authors.lastname: Blanchard
authors.forename: Wael M
authors.initials: WM
authors.lastname: Elshamy
mesh_terms: D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering