BRCA1/p220 loss triggers BRCA1-IRIS overexpression via mRNA stabilization in breast cancer cells.
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.
Mesh Terms:
BRCA1 Protein, Base Sequence, Breast Neoplasms, Carcinoma, Female, Gene Deletion, Gene Expression Regulation, Neoplastic, Humans, Molecular Sequence Data, Protein Isoforms, RNA Stability, RNA, Messenger, RNA, Small Interfering, Time Factors, Transfection, Tumor Cells, Cultured, Up-Regulation
BRCA1 Protein, Base Sequence, Breast Neoplasms, Carcinoma, Female, Gene Deletion, Gene Expression Regulation, Neoplastic, Humans, Molecular Sequence Data, Protein Isoforms, RNA Stability, RNA, Messenger, RNA, Small Interfering, Time Factors, Transfection, Tumor Cells, Cultured, Up-Regulation
Oncotarget
Date: Mar. 01, 2012
PubMed ID: 22431556
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