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Sporadic Epithelial Ovarian Cancer: Clinical Relevance of BRCA1 Inhibition in the DNA Damage and Repair Pathway

Johanne I. Weberpals, Katherine V. Clark-Knowles, Barbara C. Vanderhyden

From the Ottawa Hospital, Division of Gynaecologic Oncology, Centre for Cancer Therapeutics, Ottawa Health Research Institute; and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

Corresponding author: Johanne I. Weberpals, MD, MSc, FRCSC, The Ottawa Hospital, General Campus, Division of Gynaecologic Oncology, Room 8130, 501 Smyth Rd, Ottawa, Ontario, K1H 8LG, Canada; e-mail: jweberpals{at}ottawahospital.on.ca

Among the most promising pathways for molecular targets in sporadic epithelial ovarian cancer (SEOC) are those involving the BRCA1 protein. Because somatic mutations in BRCA1 are rare in SEOC, it was originally postulated that BRCA1 plays a limited role in the pathogenesis of this disease. However, inactivation of BRCA1 through various mechanisms is a relatively frequent event in ovarian cancer. This is important because BRCA1 is involved in the cellular response to DNA damage and repair and has an essential role in the maintenance of genomic stability. The BRCA1 tumor suppressor protein is known to interact with genes and proteins known collectively as the BRCA1 pathway, and defects in this pathway are believed to be a driving force for cancer progression. As a result, there is compelling evidence to suggest that the dysfunction of BRCA1 may be a central mechanism in all ovarian carcinogenesis, and this has clinical and molecular significance beyond the management of patients with hereditary ovarian cancer. The aim of this review is to evaluate the evidence for BRCA1 dysfunction in SEOC and to link this dysfunction to a defective DNA repair pathway and ultimately the promotion of genomic instability and tumorigenesis. Furthermore, we advocate the continued need to study BRCA1 and its pathway by prospectively correlating clinicopathologic data with molecular aberrations. This will determine whether BRCA1 has relevance as a predictive and prognostic marker in SEOC and whether aberrations in the BRCA1 pathway warrant further study as potential therapeutic targets.

Supported by a Gynecological Cancer Research Award from the Mitchell Family Fund, National Ovarian Cancer Association and Cancer Care Ontario (J.I.W.), and a grant from the Canadian Institutes of Health Research (B.C.V.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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