Nuclear factor kappaB transcription factors are coexpressed and convey a poor outcome in ovarian cancer

• Published in: Cancer 2010-07, Vol.116 (13), p.3276-3284
• Main Authors: Annunziata, Christina M, Stavnes, Helene Tuft, Kleinberg, Lilach, Berner, Aasmund, Hernandez, Lidia F, Birrer, Michael J, Steinberg, Seth M, Davidson, Ben, Kohn, Elise C
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Disease-Free Survival; Female; Gene Expression; Humans; Immunohistochemistry; Matrix Metalloproteinase 9 - metabolism; Middle Aged; NF-kappa B - genetics; NF-kappa B - metabolism; NF-kappa B p50 Subunit - metabolism; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - mortality; Prognosis; Signal Transduction - genetics; Transcription Factor RelA - metabolism; Transcription Factor RelB - metabolism; Treatment Outcome
• ISSN: 0008-543X
• DOI: 10.1002/cncr.25190

Recent work has suggested a role for nuclear factor kappaB (NF-kappaB) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-kappaB in ovarian cancer is unknown. The authors hypothesized that the NF-kappaB pathway is over activated in aggressive ovarian cancers. The levels of 3 NF-kappaB transcription factors, the activating inhibitors of NF-kappaB (IkappaB) kinases, and the NF-kappaB target matrix metalloproteinase 9 (MMP9) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel, cisplatin, and cyclophosphamide. Associations were made between NF-kappaB pathway proteins and outcome. The validation of coexpression was performed at the gene level in 2 independently collected cohorts of 185 and 153 ovarian cancers. The presence of NF-kappaB proteins in newly diagnosed advanced ovarian cancers was established, and a potential association with overall survival was identified. Transcription factors p65 and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) were coexpressed with IkappaB kinase alpha, 1 component of a key trimolecular regulatory complex. Coexpression of the NF-kappaB machinery suggested activity of NF-kappaB signaling in these ovarian tumors. A significant association of p50 with poor overall survival was observed (P = .02). MMP9 expression had the opposite association, in which patients who had tumors without MMP9 staining had the poorest prognosis (P = .01), and this association held true at the gene expression level in an independently collected cohort of 185 ovarian cancers. The deregulation of NF-kappaB activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-kappaB pathway may present an opportunity to improve outcome in the subset of women who have pathway activity.