BRCA1-mediated signaling pathways in ovarian carcinogenesis
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.
KeywordsIngenuity pathway analysis Hierarchical clustering NF-κB p53 TNF-α c-Myc
TS is thankful to the American Cancer Society (IRG #97-152-16-2), Fisher Center for Familial Cancer Center, Lombardi Comprehensive Cancer Center, Georgetown University for financial support. TS is thankful to Prof. Eliot Rosen for laboratory space, Prof. Peter Shields, Prof. Stephen Byers, Dr. Michael Johnson and Prof. Robert Clark of the Lombardi Cancer Center for their continuous support.
Conflict of interest
The authors declare no conflict of interest.
- Ali-Fehmi R, Chatterjee M, Ionan A, Levin NK, Arabi H, Bandyopadhyay S, Shah JP, Bryant CS, Hewitt SM, O’Rand MG, Alekseev OM, Morris R, Munkarah A, Abrams J, Tainsky MA (2010) Analysis of the expression of human tumor antigens in ovarian cancer tissues. Cancer Biomark 6(1):33–48. doi: 10.3233/CBM-2009-0117 PubMedGoogle Scholar
- Bonome T, Lee JY, Park DC, Radonovich M, Pise-Masison C, Brady J, Gardner GJ, Hao K, Wong WH, Barrett JC, Lu KH, Sood AK, Gershenson DM, Mok SC, Birrer MJ (2005) Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. Cancer Res 65(22):10602–10612. doi: 10.1158/0008-5472.CAN-05-2240 PubMedCrossRefGoogle Scholar
- Bronstein JM, Tiwari-Woodruff S, Buznikov AG, Stevens DB (2000) Involvement of OSP/claudin-11 in oligodendrocyte membrane interactions: role in biology and disease. J Neurosci Res 59(6):706–711. doi: 10.1002/(SICI)1097-4547(20000315)59:6<706::AID-JNR2>3.0.CO;2-D PubMedCrossRefGoogle Scholar
- Havrilesky LJ, McMahon CP, Lobenhofer EK, Whitaker R, Marks JR, Berchuck A (2001) Relationship between expression of coactivators and corepressors of hormone receptors and resistance of ovarian cancers to growth regulation by steroid hormones. J Soc Gynecol Investig 8(2):104–113.PubMedCrossRefGoogle Scholar
- Holschneider CH, Berek JS (2000) Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg Oncol 19(1):3–10. doi: 10.1002/1098-2388(200007/08)19:1<3::AID-SSU2>3.0.CO;2-S PubMedCrossRefGoogle Scholar
- Johnstone CN, Castellvi-Bel S, Chang LM, Sung RK, Bowser MJ, Pique JM, Castells A, Rustgi AK (2005) PRR5 encodes a conserved proline-rich protein predominant in kidney: analysis of genomic organization, expression, and mutation status in breast and colorectal carcinomas. Genomics 85(3):338–351. doi: 10.1016/j.ygeno.2004.11.002 PubMedCrossRefGoogle Scholar
- Murph MM, Liu W, Yu S, Lu Y, Hall H, Hennessy BT, Lahad J, Schaner M, Helland A, Kristensen G, Borresen-Dale AL, Mills GB (2009) Lysophosphatidic acid-induced transcriptional profile represents serous epithelial ovarian carcinoma and worsened prognosis. PLoS One 4(5):e5583. doi: 10.1371/journal.pone.0005583 PubMedCrossRefGoogle Scholar
- National Cancer Institute (2010) Cancer Trends Progress Report 2009/2010 UpdateGoogle Scholar
- Roh MH, Yassin Y, Miron A, Mehra KK, Mehrad M, Monte NM, Mutter GL, Nucci MR, Ning G, McKeon FD, Hirsch MS, Wa X, Crum CP (2010) High-grade fimbrial-ovarian carcinomas are unified by altered p53, PTEN and PAX2 expression. Mod Pathol 23(10):1316–1324. doi: 10.1038/modpathol.2010.119 PubMedCrossRefGoogle Scholar
- Saha T, Rih JK, Roy R, Ballal R, Rosen EM (2010) Transcriptional regulation of the base excision repair pathway by BRCA1. J Biol Chem 2010:25Google Scholar
- Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, McGinnis LK, Biggers JD, Eppig JJ, Bronson RT, Elledge SJ, Weinberg RA (1996) Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384(6608):470–474. doi: 10.1038/384470a0 PubMedCrossRefGoogle Scholar
- Skrtic A, Korac P, Kristo DR, Ajdukovic Stojisavljevic R, Ivankovic D, Dominis M (2010) Immunohistochemical analysis of NOTCH1 and JAGGED1 expression in multiple myeloma and monoclonal gammopathy of undetermined significance. Hum Pathol 41(12):1702–1710. doi: 10.1016/j.humpath.2010.05.002 PubMedCrossRefGoogle Scholar
- Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ (2007) PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem 282(35):25604–25612. doi: 10.1074/jbc.M704343200 PubMedCrossRefGoogle Scholar
- Wynendaele J, Bohnke A, Leucci E, Nielsen SJ, Lambertz I, Hammer S, Sbrzesny N, Kubitza D, Wolf A, Gradhand E, Balschun K, Braicu I, Sehouli J, Darb-Esfahani S, Denkert C, Thomssen C, Hauptmann S, Lund A, Marine JC, Bartel F (2010) An illegitimate microRNA target site within the 3′ UTR of MDM4 affects ovarian cancer progression and chemosensitivity. Cancer Res 70(23):9641–9649. doi: 10.1158/0008-5472.CAN-10-0527 PubMedCrossRefGoogle Scholar
- Yang DH, Fazili Z, Smith ER, Cai KQ, Klein-Szanto A, Cohen C, Horowitz IR, Xu XX (2006) Disabled-2 heterozygous mice are predisposed to endometrial and ovarian tumorigenesis and exhibit sex-biased embryonic lethality in a p53-null background. Am J Pathol 169(1):258–267. doi: 10.2353/ajpath.2006.060036 PubMedCrossRefGoogle Scholar
- Zabouo G, Imbert AM, Jacquemier J, Finetti P, Moreau T, Esterni B, Birnbaum D, Bertucci F, Chabannon C (2009) CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines. Breast Cancer Res 11(1):R1. doi: 10.1186/bcr2215 PubMedCrossRefGoogle Scholar