Nuclear Factor kappaB Transcription Factors Are Coexpressed and Convey a Poor Outcome in Ovarian Cancer

Cancer. 2010 Jul 1;116(13):3276-84. doi: 10.1002/cncr.25190.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Transcription Factor RelA
  • Transcription Factor RelB
  • Matrix Metalloproteinase 9