The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin.
Loading...
Embargo End Date
ICR Authors
Authors
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, PDP
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
kConFab Investigators
D'Andrea, AD
Shapiro, GI
Wiest, DL
Connolly, DC
Daly, MB
Swisher, EM
Bouwman, P
Jonkers, J
Balmaña, J
Serra, V
Johnson, N
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, PDP
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
kConFab Investigators
D'Andrea, AD
Shapiro, GI
Wiest, DL
Connolly, DC
Daly, MB
Swisher, EM
Bouwman, P
Jonkers, J
Balmaña, J
Serra, V
Johnson, N
Document Type
Journal Article
Date
2016-05
Date Accepted
2016-02-15
Abstract
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. Cancer Res; 76(9); 2778-90. ©2016 AACR.
Citation
Cancer research, 2016, 76 (9), pp. 2778 - 2790
Source Title
Publisher
ISSN
0008-5472
eISSN
1538-7445