Publications Repository

Publications Repository

View item 
  •   Home
  • ICR Divisions
  • Other ICR Research
  • View item
  • Home
  • ICR Divisions
  • Other ICR Research
  • View item
JavaScript is disabled for your browser. Some features of this site may not work without it.

The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin.

Thumbnail
View/Open
Accepted version (1.200Mb)
Date
2016-05
ICR Author
Gore, Martin
Author
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
Show allShow less
Type
Journal Article
Metadata
Show full item record
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.
URI
https://repository.icr.ac.uk/handle/internal/634
DOI
https://doi.org/10.1158/0008-5472.can-16-0186
Collections
  • Other ICR Research
Subject
kConFab Investigators
Animals
Humans
Mice
Breast Neoplasms
Ovarian Neoplasms
Cisplatin
BRCA1 Protein
Protein Isoforms
Fluorescent Antibody Technique
Blotting, Western
Immunohistochemistry
Xenograft Model Antitumor Assays
Polymerase Chain Reaction
Alternative Splicing
Drug Resistance, Neoplasm
Germ-Line Mutation
Female
Poly(ADP-ribose) Polymerase Inhibitors
Language
eng
Date accepted
2016-02-15
License start date
2016-05
Citation
Cancer research, 2016, 76 (9), pp. 2778 - 2790

Browse

All of ICR repositoryICR DivisionsBy issue dateAuthorsTitlesPublication TypesThis collectionBy issue dateAuthorsTitlesPublication Types
  • Login
  • Registered office: The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP
    A Charity, Not for Profit. Company Limited by Guarantee.
    Registered in England No. 534147. VAT Registration No. GB 849 0581 02.