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Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma.

Sakai, Wataru and Swisher, Elizabeth M and Jacquemont, Céline and Chandramohan, Kurapaty Venkatapoorna and Couch, Fergus J and Langdon, Simon P and Wurz, Kaitlyn and Higgins, Jake and Villegas, Emily and Taniguchi, Toshiyasu (2009) Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer research, 69 (16). pp. 6381-6386. ISSN 1538-7445

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Article URL: http://cancerres.aacrjournals.org/cgi/content/abst...

Abstract

Acquired platinum resistance is a serious problem in the treatment of ovarian carcinomas. However, the mechanism of the drug resistance has not been elucidated. Here, we show functional significance of restoration of BRCA2 protein by secondary BRCA2 mutations in acquired drug resistance of BRCA2-mutated ovarian carcinoma. Three ovarian cancer cell lines (PEO1, PEO4, and PEO6) were derived from a BRCA2 mutation [5193C>G (Y1655X)] carrier with ovarian carcinoma with acquired cisplatin resistance and a secondary BRCA2 mutation [5193C>T (Y1655Y)] that canceled the inherited mutation. PEO1 was BRCA2 deficient and sensitive to cisplatin and a poly(ADP-ribose) polymerase inhibitor, AG14361, whereas PEO4 was resistant. PEO4 and PEO6, derived from ascites at the time of relapse with cisplatin resistance, had the secondary mutation and were BRCA2 proficient. In vitro cisplatin/AG14361 selection of PEO1 led to restoration of BRCA2 due to another secondary BRCA2 mutation. BRCA2 depletion sensitized BRCA2-restored PEO1 clones and PEO4 to cisplatin/AG14361. Thus, restoration of BRCA2 due to secondary BRCA2 mutation is involved in acquired drug resistance of BRCA2-mutated ovarian carcinoma.

Item Type: Article
Additional Information: This article is available to subscribers only via the URL above for the first 12 months following publication.
DOI: 10.1158/0008-5472.CAN-09-1178
PubMed ID: 19654294
NIHMSID: NIHMS145748
PMCID: PMC2754824
Grant Numbers: R01 CA125636-03, P30 CA015704-35, K08 CA096610-01, P50 CA116201-050002, R01 CA116167-03
Keywords or MeSH Headings: * BRCA2 Protein/genetics* * BRCA2 Protein/metabolism * BRCA2 Protein/physiology* * Base Sequence * Carcinoma/genetics* * Carcinoma/metabolism * Cell Survival/drug effects * Cell Survival/genetics * Cisplatin/pharmacology * Cisplatin/therapeutic use * DNA Mutational Analysis * Drug Resistance, Neoplasm/genetics* * Drug Resistance, Neoplasm/physiology * Female * Humans * Mutation/physiology * Open Reading Frames/drug effects * Open Reading Frames/genetics * Ovarian Neoplasms/genetics* * Ovarian Neoplasms/metabolism * RNA, Small Interfering/pharmacology * Tumor Cells, Cultured
Subjects: Cellular and Organismal Processes > Genetic processes > Mutation
Diseases > Solid tumors > Ovarian cancer
Therapeutics > Drug Therapy
Depositing User: Library Staff
Date Deposited: 15 Sep 2009 21:40
Last Modified: 14 Feb 2012 14:42
URI: http://authors.fhcrc.org/id/eprint/331

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