title: IKK-ε coordinates invasion and metastasis of ovarian cancer.
abstract: Inhibitor of IκB kinases (IKK) are key regulators of NF-κB signaling. Three IKK isoforms-α, β, and ε-have been linked to oncogenesis, yet the precise components of NF-κB signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKK-ε expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumors (P = 0.03). Therefore, we hypothesized that IKK-ε drives ovarian cancer metastasis. IKK-ε was identified previously as a breast cancer oncogene and was associated with poor clinical outcome in ovarian cancer. We now define an ovarian cancer-specific IKK-ε-regulated gene expression signature using stably expressed short hairpin RNA targeting IKK-ε. Pathway analysis of the signature indicated that IKK-ε regulates expression of genes involved in cell motility and inflammation. We further showed that IKK-ε depletion in metastatic ovarian cancer cell lines decreased growth, adhesion, and invasion. Consistently, human xenografts depleted of IKK-ε in mice showed decreased aggressiveness, whereas overexpression of IKK-ε in a less invasive ovarian cancer cell line increased metastasis in vivo. Taken together, these data provide evidence that IKK-ε is a key coordinator of invasion and metastasis programs in ovarian cancer. Inhibition of IKK-ε signaling thus emerges as a viable therapeutic strategy in women whose ovarian cancer shows aberrant activation of this pathway.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hsu
authors.forename: Marianne
authors.initials: M
authors.lastname: Kim
authors.forename: Lidia
authors.initials: L
authors.lastname: Hernandez
authors.forename: Valentina
authors.initials: V
authors.lastname: Grajales
authors.forename: Anne
authors.initials: A
authors.lastname: Noonan
authors.forename: Miriam
authors.initials: M
authors.lastname: Anver
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
mesh_terms: D000818:Animals; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D046888:Tissue Array Analysis; D059467:Transcriptome; D014183:Transplantation, Heterologous
chemical_list: D051550:I-kappa B Kinase