title: The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer.
abstract: This study compares Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1) expression as predictive markers and evaluates the in vitro enhancement of platinum sensitivity using targeted agents in sporadic ovarian cancer (OC). A retrospective study was performed of advanced stage OC patients receiving platinum-based chemotherapy. BRCA1 and ERCC1 mRNA expression was determined from frozen tissue of 51 patients. Median overall survival (OS) was longer for patients with lower BRCA1 vs. higher BRCA1 (46 vs.33 months, p = 0.03). High BRCA1 was predictive of poorer OS specifically in patients with residual disease (RD) <2 cm (p = 0.03). There was a non-significant association for patients with lower ERCC1 and RD <2 cm in favor of improved OS and time to progression. Patients who expressed higher levels of both BRCA1 and ERCC1 mRNA had a shorter OS compared to patients with lower levels of either or both transcript (33 vs.46 months, p = 0.04). When Cox proportional modeling was used by representing BRCA1 and ERCC1 mRNA expression as a continuous variable, both emerge as potential predictors of survival. OC cell lines were exposed to chemotherapy in combination with DNA repair pathway inhibitors and cell viability was assessed. In vitro histone deacetylase (HDAC) inhibition increased the sensitivity of A2780s/cp cells to cisplatin and carboplatin but not to taxol, coincident with a significant decrease in BRCA1 and ERCC1 expression, suggesting that this compound directly targets DNA repair. In summary, this study shows that low BRCA1 and ERCC1 expression correlate with improved survival in advanced OC and HDAC inhibition induces synergistic cytotoxicity with platinum in vitro.
authors.affiliation: Division of Gynaecologic Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada. jweberpals@ottawahospital.on.ca
authors.forename: Johanne
authors.initials: J
authors.lastname: Weberpals
authors.forename: Kyla
authors.initials: K
authors.lastname: Garbuio
authors.forename: Anna
authors.initials: A
authors.lastname: O'Brien
authors.forename: Katherine
authors.initials: K
authors.lastname: Clark-Knowles
authors.forename: Steve
authors.initials: S
authors.lastname: Doucette
authors.forename: Olga
authors.initials: O
authors.lastname: Antoniouk
authors.forename: Glenwood
authors.initials: G
authors.lastname: Goss
authors.forename: Jim
authors.initials: J
authors.lastname: Dimitroulakos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D019313:BRCA1 Protein / Q000096:biosynthesis* / Q000235:genetics; D016190:Carboplatin / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004720:Endonucleases / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; D016190:Carboplatin; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin