Functional & Integrative Genomics

, Volume 12, Issue 1, pp 63–79

BRCA1-mediated signaling pathways in ovarian carcinogenesis

Original Paper

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.

Keywords

Ingenuity pathway analysis Hierarchical clustering NF-κB p53 TNF-α c-Myc 

Supplementary material

10142_2011_251_MOESM1_ESM.pdf (985 kb)
Supplementary Fig 1Network of upregulated genes central to p53 and Myc in BRCA1-SKOV3. Using Ingenuity Pathway Knowledge Base, we were able to deduce number of network of genes centered with the p53 tumor suppressor and Myc oncogene that was significantly (p < 0.05) induced due to stable expression of wtBRCA1 in SKOV3. The color intensities indicate the increase in fold expression levels of the respective genes. Usages of arrows, lines, various shapes, and labels along with the descriptive notes and edges highlight the nature of the relationships among the functional genes in the network. (PDF 984 kb)
10142_2011_251_MOESM2_ESM.pdf (1 mb)
Supplementary Fig 2Network of downregulated genes central to TNF, ERBB2, and Myc in BRCA1-SKOV3. Using Ingenuity Pathway Knowledge Base, we were able to deduce number of network of genes centered with TNF, the inflammatory cytokine, ERBB2, the receptor tyrosine kinase and Myc oncogene that were significantly (p < 0.05) knocked down due to stable expression of wtBRCA1 in SKOV3 cells. See supplementary Fig. 1 (legend) for other information. (PDF 1024 kb)
10142_2011_251_MOESM3_ESM.pdf (996 kb)
Supplementary Fig 3Network of upregulated genes central to IL-6 and ERK1 in BRCA1-SKOV3. Using Ingenuity Pathway Knowledge Base, we were able to deduce number of network of genes centered with IL6 and ERK1 that were significantly (p < 0.05) induced due to stable expression of wtBRCA1 in SKOV3. See Supplementary Fig. 1 (legend) for other information. (PDF 996 kb)
10142_2011_251_MOESM4_ESM.pdf (127 kb)
Supplementary Fig 4Network of upregulated genes central to β-estradiol, RNA polymerase 1 and progesterone in BRCA1-SKOV3. Using Ingenuity Pathway Knowledge Base, we were able to deduce number of network of genes centered with β-estradiol, RNA polymerase 1 and progesterone that were significantly (p < 0.05) induced due to stable expression of wtBRCA1 in SKOV3. See Supplementary Fig. 1 (legend) for other information. (PDF 126 kb)
10142_2011_251_MOESM5_ESM.pdf (856 kb)
Supplementary Fig 5Network of upregulated genes central to FOXA2 in BRCA1-SKOV3. Using Ingenuity Pathway Knowledge Base, we were able to deduce number of network of genes centered with Forkhead Box A2 (FOXA2) that were significantly (p < 0.05) induced due to stable expression of wtBRCA1 in SKOV3 cells. See Supplementary Fig. 1 (legend) for other information. (PDF 855 kb)
10142_2011_251_MOESM6_ESM.pdf (970 kb)
Supplementary Fig 6Network of upregulated genes central to Cyclin D2, TGF-β, and Smad3 in BRCA1-SKOV3. Using Ingenuity Pathway Knowledge Base, we were able to deduce number of network of genes centered with cyclin D2, TGF-β, and Smad3 that were significantly (p < 0.05) induced due to stable expression of wtBRCA1 in SKOV3 cells. See Supplementary Fig. 1 (legend) for other information. (PDF 969 kb)
10142_2011_251_MOESM7_ESM.pdf (31 kb)
Supplementary Table 1List of genes in each cluster (Fig. 2) with fold change and p values (PDF 30 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Oncology, Lombardi Comprehensive Cancer CenterGeorgetown University School of MedicineWashingtonUSA
  2. 2.Department of Biostatistics, Bioinformatics and BiomathematicsGeorgetown University School of MedicineWashingtonUSA
  3. 3.Department of Biochemistry, Cellular and Molecular BiologyGeorgetown University School of MedicineWashingtonUSA

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