Abstract 1479: IKK-epsilon contributes to the malignant progression of ovarian cancer

Abstract

Abstract Background and significance: The mechanism through which the NF-κB pathway affects the initiation, propagation and dissemination of ovarian cancer is unknown. I-κB kinases (IKKs) are key regulators of NF-κB signaling. Three IKK isoforms – α, β and ∈ – have been linked to oncogenesis, yet the precise components of NF-κB signaling mechanisms in ovarian cancer have not yet been dissected. IKK∈ was identified as an oncogene in breast cancer and has been associated with poor clinical outcome in ovarian cancer. This IKK isoform can regulate the innate immune response via activation of interferon-response factors, or can signal through classical NF-κB mechanisms by inactivating CYLD, a negative regulator of the pathway. Therefore, the molecular context is key to determining which oncogenic pathway is activated and how the signals will ultimately affect the cancer cel We hypothesized that IKK∈ drives ovarian cancer growth and metastasis. Methods: The expression of IKKe was determined in primary ovarian cancer specimens and human ovarian cancer cell lines. Ovarian cancer cell lines were depleted of IKKe using RNA interference and tested in functional assays, including anchorage-independent growth, basement membrane invasion, and heterotypic cell adhesion. Orthotopic xenograft mouse models were used to determine the role of IKKe in metastasis in vivo. Gene expression microarrays established an IKKe-specific signature in ovarian cancer. Results: We surveyed 120 ovarian cancer specimens (42 primary carcinomas, 78 solid metastases) for IKK∈ expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumor sites (p=0.03). RNA interference targeting IKK∈ in a panel of 5 metastatic ovarian cancer cell lines inhibited cell growth and prevented colony formation in soft agar. An ovarian cancer-specific IKK∈-regulated gene expression signature was identified using stably expressed shRNA targeting IKK∈. Pathway analysis of the signature indicated that IKK∈ regulates the expression of genes essential to diverse processes known to contribute to the malignancy of ovarian cancer, including TGFb and HIF1a pathways. Orthotopic xenograft experiments in mice demonstrated decreased aggressiveness of IKK∈-depleted ovarian cancer cells. Conclusion: These data provide evidence that IKK∈ plays a key role in ovarian cancer metastasis. Understanding IKK∈-regulated signaling in ovarian cancer will identify novel pathway interactions for context-specific therapeutics in the poor prognostic group of women whose ovarian cancers over-express IKK∈. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1479. doi:10.1158/1538-7445.AM2011-1479