Molecular and Cellular Pathobiology IKK-« Coordinates Invasion and Metastasis of Ovarian Cancer

Inhibitor of IkB kinases (IKK) are key regulators of NF-kB signaling. Three IKK isoforms—a, b, and e—have been linked to oncogenesis, yet the precise components of NF-kB signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKK-e expression. Notably, cytoplasmic expression was elevated inmetastatic lesions relative to primary tumors (P1⁄4 0.03). Therefore, we hypothesized that IKK-e drives ovarian cancer metastasis. IKK-e 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-e–regulated gene expression signature using stably expressed short hairpin RNA targeting IKK-e. Pathway analysis of the signature indicated that IKK-e regulates expression of genes involved in cell motility and inflammation. We further showed that IKK-e depletion in metastatic ovarian cancer cell lines decreased growth, adhesion, and invasion. Consistently, human xenografts depleted of IKK-e in mice showed decreased aggressiveness, whereas overexpression of IKK-e in a less invasive ovarian cancer cell line increased metastasis in vivo. Taken together, these data provide evidence that IKK-e is a key coordinator of invasion and metastasis programs in ovarian cancer. Inhibition of IKK-e signaling thus emerges as a viable therapeutic strategy in womenwhose ovarian cancer shows aberrant activation of this pathway. Cancer Res; 72(21); 5494–504. 2012 AACR.