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

Authors

  • Christina M. Annunziata MD, PhD,

    Corresponding author
    1. Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    • Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 12N226, 10 Center Drive, Bethesda, MD 20892-1906
    Search for more papers by this author
    • Fax: (301) 402-0172

  • Helene Tuft Stavnes PhD,

    1. Division of Pathology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway
    Search for more papers by this author
  • Lilach Kleinberg PhD,

    1. Division of Pathology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway
    Search for more papers by this author
  • Aasmund Berner MD, PhD,

    1. Division of Pathology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway
    Search for more papers by this author
  • Lidia F. Hernandez MS,

    1. Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Michael J. Birrer MD, PhD,

    1. Gynecologic Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts
    Search for more papers by this author
  • Seth M. Steinberg PhD,

    1. Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Ben Davidson MD, PhD,

    1. Division of Pathology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway
    2. Faculty Division, Radiumhospitalet Medical Faculty, University of Oslo, Oslo, Norway
    Search for more papers by this author
  • Elise C. Kohn MD

    1. Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author

  • This article is US Government work and, as such, is in the public domain in the United States of America.

Abstract

BACKGROUND:

Recent work has suggested a role for nuclear factor κB (NF-κB) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-κB in ovarian cancer is unknown. The authors hypothesized that the NF-κB pathway is over activated in aggressive ovarian cancers.

METHODS:

The levels of 3 NF-κB transcription factors, the activating inhibitors of NF-κB (IκB) kinases, and the NF-κB 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-κB 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-κB 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 IκB kinase α, 1 component of a key trimolecular regulatory complex. Coexpression of the NF-κB machinery suggested activity of NF-κB 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-κB activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-κB pathway may present an opportunity to improve outcome in the subset of women who have pathway activity. Cancer 2010. © 2010 American Cancer Society.

Ancillary