Abstract 1573: Non-canonical NF-kappaB signaling in the tumor microenvironment in relation to ovarian cancer survival
Authors: Hufnagel Demetra , Wilson Andrew J. , Saxon Jamie , Blackwell Timothy , Khabele Dineo , Crispens Marta A. , Beeghly-Fadiel Alicia , Yull Fiona 
Published: August 2019

Introduction: Despite advances in treatment, ovarian cancer associated mortality has not substantially improved over the last 50 years. Understanding mechanisms that underlie disease progression is crucial to the development of new treatments for ovarian cancer. Mediated by a family of transcription factors, the canonical and non-canonical nuclear factor-kappaB signaling pathways have known roles in cell proliferation, as well as immune, inflammatory, and neoplastic processes. Non-canonical NF-kappaB signaling requires processing of a cytoplasmic p100/RelB dimer to a mature p52/RelB complex, capable of nuclear translocation to activate transcription of target genes. Prior studies on canonical NF-kappaB expression and ovarian cancer survival have been inconsistent, but no studies to date have evaluated the role of non-canonical NF-kappaB transcription factors.

Methods: We conducted immunohistochemical staining for p52, a component of the non-canonical NF-kappaB signaling pathway, on a clinically annotated tissue microarray of ovarian tumors collected from 1994-2004 at the Vanderbilt University Medical Center. Nuclear and cytoplasmic p52 staining in tumors was semi-quantified by H-score and expression was dichotomized at median values. Associations with progression-free survival (PFS) and overall survival (OS) were quantified by hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional-hazards regression.

Results: Among 194 ovarian cancer cases, p52 expression was predominantly cytoplasmic, with a relatively smaller proportion of tumor cells showing nuclear staining (median H-scores: 135.6 vs. 1.0). Cytoplasmic and nuclear p52 H-scores were significantly higher among high grade, advanced stage, and serous tumors (all Wilcoxon rank sum p&lt;0.01). Kaplan-Meier survival analysis showed that cases with high nuclear p52 expression had significantly shorter time to disease progression (5-year PFS high vs. low: 72% vs. 17%, log-rank p&lt;0.001). In regression models that included adjustment for age, stage, grade, and histologic subtype, high nuclear p52 was associated with a more than two-fold shorter PFS (HR 2.30, 95% CI 1.44-4.67). Significance of this finding was unaltered by additional adjustment for race, debulking, and platinum sensitivity (HR 2.26, 95% CI 1.15-4.45). In contrast, significant associations between high nuclear p52 and worse OS, and all associations for cytoplasmic p52 staining were attenuated after adjustment for clinical covariates.

Conclusions: This is the first study to demonstrate that nuclear p52, representing active non-canonical NF-kappaB signaling, may be an independent prognostic factor for epithelial ovarian cancer. Thus, interventions that inhibit non-canonical NF-kappaB signaling should be explored as novel therapies to limit ovarian cancer progression.

Citation Format: Demetra Hufnagel, Andrew J. Wilson, Jamie Saxon, Timothy Blackwell, Dineo Khabele, Marta A. Crispens, Alicia Beeghly-Fadiel, Fiona Yull. Non-canonical NF-kappaB signaling in the tumor microenvironment in relation to ovarian cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1573.