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Cancer Res. 2016 May 1;76(9):2778-90. doi: 10.1158/0008-5472.CAN-16-0186.

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

Author information

1
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
2
High Risk and Cancer Prevention Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain. Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
3
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
4
Division of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
5
Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
6
Department of Obstetrics and Gynecology and Medicine, University of Washington, Seattle, Washington.
7
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
8
Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
9
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
10
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
11
University of Edinburgh Cancer Research UK Centre, MRC IGMM, Edinburgh, United Kingdom.
12
VIB Vesalius Research Center, University of Leuven, Leuven, Belgium.
13
QIMR Berghofer Medical Research Institute, Herston, Australia.
14
Departments of Cancer Epidemiology and Oncology, Lund University, Lund, Sweden.
15
Human Genetics Group and Human Genotyping Unit Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
16
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
17
Royal Marsden NHS Foundation Trust, London, United Kingdom.
18
University of California San Francisco, Cancer Risk Program, San Francisco, California.
19
Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Tel Hashomer, Israel.
20
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
21
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
22
Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Pediatrics, Children's Hospital and Harvard Medical School, Boston, Massachusetts.
23
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
24
Risk Assessment Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
25
High Risk and Cancer Prevention Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
26
Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
27
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. neil.johnson@fccc.edu.

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.

PMID:
27197267
PMCID:
PMC4874568
DOI:
10.1158/0008-5472.CAN-16-0186
[Indexed for MEDLINE]
Free PMC Article

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