Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis

Demetra H Hufnagel,Marta A Crispens,Timothy S Blackwell,Jaclyn Watkins,Jamie Saxon,Fiona E Yull,Dineo Khabele,Andrew J Wilson,Alicia Beeghly-Fadiel

doi:10.1186/s40364-020-00227-y

Abstract

BackgroundThe canonical and non-canonical nuclear factor-kappaB (NF-κB) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival. Although a number of in vitro and in vivo studies have demonstrated mechanisms by which non-canonical NF-κB signaling potentially contributes to ovarian cancer progression, a prognostic association has yet to be shown in the clinical context.MethodsWe assayed p65 and p52 (major components of the canonical and non-canonical NF-κB pathways) by immunohistochemistry in epithelial ovarian tumor samples; nuclear and cytoplasmic staining were semi-quantified by H-scores and dichotomized at median values. Associations of p65 and p52 with progression-free survival (PFS) and overall survival (OS) were quantified by Hazard Ratios (HR) from proportional-hazards regression.ResultsAmong 196 cases, median p52 and p65 H-scores were higher in high-grade serous cancers. Multivariable regression models indicated that higher p52 was associated with higher hazards of disease progression (cytoplasmic HR: 1.54; nuclear HR: 1.67) and death (cytoplasmic HR: 1.53; nuclear HR: 1.49), while higher nuclear p65 was associated with only a higher hazard of disease progression (HR: 1.40) in unadjusted models. When cytoplasmic and nuclear staining were combined, p52 remained significantly associated with increased hazards of disease progression (HR: 1.91, p = 0.004) and death (HR: 1.70, p = 0.021), even after adjustment for p65 and in analyses among only high-grade serous tumors.ConclusionsThis is the first study to demonstrate that p52, a major component of non-canonical NF-κB signaling, may be an independent prognostic factor for epithelial ovarian cancer, particularly high-grade serous ovarian cancer. Approaches to inhibit non-canonical NF-κB signaling should be explored as novel ovarian cancer therapies are needed.

Highlights

The canonical and non-canonical nuclear factor-kappaB (NF-κB) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival
Ovarian cancer tissue microarray We evaluated a validated TMA constructed from primary ovarian tumor samples from the Vanderbilt University Medical Center (VUMC) Tissue Repository for Ovarian Cancer (TROC) [36, 37]
Cases had a median age of diagnosis of 58.3 years, median progression-free survival of 1.6 years, and median overall survival of 3.6 years

Summary

Introduction

The canonical and non-canonical nuclear factor-kappaB (NF-κB) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival. While overall rates of death from cancer have dramatically declined over the past few decades, mortality from ovarian cancer has hovered around 10 women per 100,000 for the last 50 years [2, 3]. While most patients have a dramatic initial response to first-line platinum and taxane-based chemotherapies, the majority will develop recurrent and treatment-resistant disease [1, 6]. This is relevant to high-grade serous ovarian cancer, the most common and deadliest of the five main subtypes when classified by grade and histology: high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous tumors [7,8,9,10]. The development of additional treatment modalities to improve ovarian cancer survival requires further understanding of the pathogenesis of this disease

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