Nuclear factor kappaB transcription factors are coexpressed and convey a poor outcome in ovarian cancer.
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.
Annunziata
Christina M
CM
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1906, USA. annunzic@mail.nih.gov
Stavnes
Helene Tuft
HT
Kleinberg
Lilach
L
Berner
Aasmund
A
Hernandez
Lidia F
LF
Birrer
Michael J
MJ
Steinberg
Seth M
SM
Davidson
Ben
B
Kohn
Elise C
EC
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism; D016896:Treatment Outcome
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D020780:Matrix Metalloproteinase 9