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.

Original languageEnglish
Pages (from-to)2778-2790
Number of pages13
JournalCancer Research
Issue number9
StatePublished - 1 May 2016
Externally publishedYes


FundersFunder number
Asociacion Española contra el Cancer
OC130212 Department of Defense Ovarian AcademyP50 CA83636
Susan G. Komen Career Catalyst AwardCCR12226280
Wendy Feuer Ovarian Cancer Research Fund
National Institutes of Health5P30 CA006927
National Institutes of Health
National Cancer InstituteP50CA083638, R21CA191690
National Cancer Institute
Fox Chase Cancer Center
Instituto de Salud Carlos IIIPI12/02606
Instituto de Salud Carlos III
Sociedad Española de Oncología Médica


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