TY - JOUR
T1 - The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin
AU - kConFab Investigators
AU - Wang, Yifan
AU - Bernhardy, Andrea J.
AU - Cruz, Cristina
AU - Krais, John J.
AU - Nacson, Joseph
AU - Nicolas, Emmanuelle
AU - Peri, Suraj
AU - Van Der Gulden, Hanneke
AU - Van Der Heijden, Ingrid
AU - O'Brien, Shane W.
AU - Zhang, Yong
AU - Harrell, Maribel I.
AU - Johnson, Shawn F.
AU - Dos Reis, Francisco J.Candido
AU - Pharoah, Paul D.P.
AU - Karlan, Beth
AU - Gourley, Charlie
AU - Lambrechts, Diether
AU - Chenevix-Trench, Georgia
AU - Olsson, Håkan
AU - Benitez, Javier J.
AU - Greene, Mark H.
AU - Gore, Martin
AU - Nussbaum, Robert
AU - Sadetzki, Siegal
AU - Gayther, Simon A.
AU - Kjaer, Susanne K.
AU - D'Andrea, Alan D.
AU - Shapiro, Geoffrey I.
AU - Wiest, David L.
AU - Connolly, Denise C.
AU - Daly, Mary B.
AU - Swisher, Elizabeth M.
AU - Bouwman, Peter
AU - Jonkers, Jos
AU - Balmaña, Judith
AU - Serra, Violeta
AU - Johnson, Neil
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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-Δ11q 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-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q 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-Δ11q 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.
AB - 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-Δ11q 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-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q 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-Δ11q 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.
UR - http://www.scopus.com/inward/record.url?scp=84969540916&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-0186
DO - 10.1158/0008-5472.CAN-16-0186
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C2 - 27197267
AN - SCOPUS:84969540916
SN - 0008-5472
VL - 76
SP - 2778
EP - 2790
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -