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The BRCA1-Δ11q alte...
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Wang, YifanFox Chase Cancer Center
(author)
The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin
- Article/chapterEnglish2016
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LIBRIS-ID:oai:lup.lub.lu.se:1e41ee44-78fb-42f7-b265-ff2174920ec2
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https://lup.lub.lu.se/record/1e41ee44-78fb-42f7-b265-ff2174920ec2URI
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https://doi.org/10.1158/0008-5472.CAN-16-0186DOI
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Language:English
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Summary in:English
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
Notes
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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.
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Bernhardy, Andrea J.Fox Chase Cancer Center
(author)
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Cruz, CristinaVall d'Hebron University Hospital
(author)
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Krais, John J.Fox Chase Cancer Center
(author)
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Nacson, JosephFox Chase Cancer Center
(author)
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Nicolas, EmmanuelleFox Chase Cancer Center
(author)
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Peri, SurajFox Chase Cancer Center
(author)
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Van Der Gulden, HannekeNetherlands Cancer Institute
(author)
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Van Der Heijden, IngridNetherlands Cancer Institute
(author)
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O'Brien, Shane W.Fox Chase Cancer Center
(author)
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Zhang, Yong
(author)
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Harrell, Maribel I.
(author)
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Johnson, Shawn F.
(author)
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Candido Dos Reis, Francisco J.
(author)
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Pharoah, Paul D P
(author)
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Karlan, Beth
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Gourley, Charlie
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Lambrechts, Diether
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Chenevix-Trench, Georgia
(author)
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Olsson, HåkanLund University,Lunds universitet,Medicinsk onkologi,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumörmikromiljö,Institutionen för kliniska vetenskaper, Lund,Medical oncology,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Tumor microenvironment,Department of Clinical Sciences, Lund(Swepub:lu)onk-hol
(author)
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Benitez, Javier J.
(author)
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Greene, Mark H.
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Gore, Martin
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Nussbaum, Robert
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Sadetzki, Siegal
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Gayther, Simon A.
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Kjaer, Susanne K.
(author)
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K'Con Fab, Fab
(author)
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D'Andrea, Alan D.
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Shapiro, Geoffrey I.
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Wiest, David L.
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Connolly, Denise C.
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Daly, Mary B.
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Swisher, Elizabeth M.
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Bouwman, Peter
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Jonkers, Jos
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Balmaña, Judith
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Serra, Violeta
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Johnson, Neil
(author)
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Fox Chase Cancer CenterVall d'Hebron University Hospital
(creator_code:org_t)
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In:Cancer Research76:9, s. 2778-27900008-5472
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Wang, Yifan
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Bernhardy, Andre ...
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Cruz, Cristina
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Krais, John J.
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Nacson, Joseph
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Nicolas, Emmanue ...
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Peri, Suraj
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Van Der Gulden, ...
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Van Der Heijden, ...
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O'Brien, Shane W ...
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Zhang, Yong
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Harrell, Maribel ...
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Johnson, Shawn F ...
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Candido Dos Reis ...
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Pharoah, Paul D ...
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Karlan, Beth
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Gourley, Charlie
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Lambrechts, Diet ...
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Chenevix-Trench, ...
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Olsson, Håkan
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Benitez, Javier ...
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Greene, Mark H.
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Gore, Martin
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Nussbaum, Robert
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Sadetzki, Siegal
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Gayther, Simon A ...
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Kjaer, Susanne K ...
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K'Con Fab, Fab
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D'Andrea, Alan D ...
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Shapiro, Geoffre ...
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Wiest, David L.
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Connolly, Denise ...
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Daly, Mary B.
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Swisher, Elizabe ...
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Bouwman, Peter
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Jonkers, Jos
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Balmaña, Judith
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Serra, Violeta
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Johnson, Neil
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- MEDICAL AND HEALTH SCIENCES
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Cancer Research
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Lund University