BRCA1-mediated signaling pathways in ovarian carcinogenesis

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Road NW, Washington, DC 20057, USA.
Functional & Integrative Genomics (Impact Factor: 2.48). 09/2011; 12(1):63-79. DOI: 10.1007/s10142-011-0251-2
Source: PubMed


The link between loss or defect in functional BRCA1 and predisposition for development of ovarian and breast cancer is well established. Germ-line mutations in BRCA1 are responsible for both hereditary breast and ovarian cancer, which is around 5-10% for all breast and 10-15% of all ovarian cancer cases. However, majority of cases of ovarian cancer are sporadic in nature. The inactivation of cellular BRCA1 due to mutations or loss of heterozygosity is one of the most commonly observed events in such cases. Complement-resistant retroviral BRCA1 vector, MFG-BRCA1, is the only approved gene therapy for ovarian cancer patients by the Federal and Drug Administration. Given the limited available information, there is a need to evaluate the effects of BRCA1 on the global gene expression pattern for better understanding the etiology of the disease. Here, we use Ingenuity Pathway Knowledge Base to examine the differential pattern of global gene expression due to stable expression of BRCA1 in the ovarian cancer cell line, SKOV3. The functional analysis detected at least five major pathways that were significantly (p < 0.05) altered. These include: cell to cell signaling and interaction, cellular function and maintenance, cellular growth and proliferation, cell cycle and DNA replication, and recombination repair. In addition, we were able to detect several biologically relevant genes that are central for various signaling networks involved in cellular homeostasis; TGF-β1, TP53, c-MYC, NF-κB and TNF-α. This report provides a comprehensive rationale for tumor suppressor function(s) of BRCA1 in ovarian carcinogenesis.

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    • "To predict the cellular signaling pathways, the 231 differentially expressed proteins with high confidence were analyzed with IPA [17] [18] [19] and MetaCore [20] [21]. According to the prediction, 21.6% (50/231) of proteins were involved in the pathways of cellular movement, 17.3% (40/231) were found to play roles in cell to cell signaling and interactions, 21.2% (49/231) participated in cell death pathways, 16% (37/231) were involved in cell morphology, and 22.9% (53/231) were found in signaling pathways that regulate cell growth and proliferation (Fig. 2B). "
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    • "RNA isolation, cDNA synthesis, gene chip hybridizations, and data analysis were performed as described earlier [32]. The empty vector and the stable BRCA1 clone in SKOV3 cells that were used to generate microarray data thoroughly described in our earlier manuscript [32]. The gene chips used for these experiments were Human Genome U133 Plus 2.0 Array. "
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