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Wang Y , Bernhardy AJ , Cruz C , Krais JJ , Nacson J , Nicolas E , Peri S , van der Gulden H , van der Heijden I , O'Brien SW , Zhang Y , Harrell MI , Johnson SF , Candido Dos Reis FJ , Pharoah PD , Karlan B , Gourley C , Lambrechts D , Chenevix-Trench G , Olsson H , Benitez JJ , Greene MH , Gore M , Nussbaum R , Sadetzki S , Gayther SA , Kjaer SK , D'Andrea AD , Shapiro GI , Wiest DL , Connolly DC , Daly MB , Swisher EM , Bouwman P , Jonkers J , Balmana J , Serra V , Johnson N
The BRCA1-Delta11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin
Cancer Res. 2016 May 1;76(9) :2778-90
PMID: 27197267    PMCID: PMC4874568   
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Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Delta11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Delta11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Delta11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo Furthermore, spliceosome inhibitors reduced BRCA1-Delta11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778-90. (c)2016 AACR.
Wang, Yifan Bernhardy, Andrea J Cruz, Cristina Krais, John J Nacson, Joseph Nicolas, Emmanuelle Peri, Suraj van der Gulden, Hanneke van der Heijden, Ingrid O'Brien, Shane W Zhang, Yong Harrell, Maribel I Johnson, Shawn F Candido Dos Reis, Francisco J Pharoah, Paul D P Karlan, Beth Gourley, Charlie Lambrechts, Diether Chenevix-Trench, Georgia Olsson, Hakan Benitez, Javier J Greene, Mark H Gore, Martin Nussbaum, Robert Sadetzki, Siegal Gayther, Simon A Kjaer, Susanne K kConFab Investigators D'Andrea, Alan D Shapiro, Geoffrey I Wiest, David L Connolly, Denise C Daly, Mary B Swisher, Elizabeth M Bouwman, Peter Jonkers, Jos Balmana, Judith Serra, Violeta Johnson, Neil R21 CA191690/CA/NCI NIH HHS/United States United States Cancer Res. 2016 May 1;76(9):2778-90. doi: 10.1158/0008-5472.CAN-16-0186.