BRCA1-mediated signaling pathways in ovarian carcinogenesis

Abstract

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.

BRCA1 Regulates Follistatin Function in Ovarian Cancer and Human Ovarian Surface Epithelial Cells

“…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.…”

“…The gene chips used for these experiments were Human Genome U133 Plus 2.0 Array. All microarray data was MIAME (Minimum Information About a Microarray Experiment) compliant and the raw data has been deposited in Gene Expression Omnibus database (GEO) as describe in our earlier manuscript [32]. The accession number for this submission is GSE30296.…”

“…The accession number for this submission is GSE30296. Hierarchical clustering of the selected genes was done as before [32].…”

Roles of Estrogens in Prostate Cancer Development via the Modulation of DNA-Repair System

“…The p53 is mutated and/or deleted in almost half of human cancers during carcinogenesis [60,61], which fails to function normally. BRCA1 also plays a part in DNA recombination and repair processes related to maintenance of genomic integrity, and control of cell growth [62]. In general, normal cells show a good balance of the various mechanisms of the DNA repair.…”

Defective DNA repair systems and the development of breast and prostate cancer

“…BRCA1 regulates the expression of several genes identified as having key roles in breast and ovarian cancer risk. BRCA1 also participates in DNA repair and recombination processes related to the maintenance of genomic integrity and the control of cell proliferation (14). As most BRCA1 mutant cancers are hormone receptor-negative, hormonal factors may contribute to the etiology of BRCA1 mutant cancers (15,16).…”