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Functional Restoration of BRCA2 Protein by Secondary BRCA2 Mutations in BRCA2-Mutated Ovarian Carcinoma

¹ Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center; Departments of ² Obstetrics and Gynecology, ³ Medicine, and ⁴ Genome Sciences, University of Washington, Seattle, Washington; ⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and ⁶ Edinburgh Cancer Research Centre, Department of Pathology, University of Edinburgh, Edinburgh, United Kingdom

Requests for reprints: Toshiyasu Taniguchi, Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, C1-015, Seattle, WA 98109-1024. Phone: 206-667-7283; Fax: 206-667-5815; E-mail: ttaniguc{at}fhcrc.org.

Key Words: BRCA2 • cisplatin • drug resistance • ovarian cancer • PARP inhibitor

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. [Cancer Res 2009;69(16):6381–6]