Retinoid X receptor gamma (RXRG) is an independent prognostic biomarker in ER-positive invasive breast cancer

Abstract

Background Retinoid X Receptor Gamma (RXRG) is a member of the nuclear receptor superfamily and plays a role in tumour suppression. This study aims to explore the prognostic significance of RXRG in breast cancer. Methods Primary breast cancer tissue microarrays (n = 923) were immuno-stained for RXRG protein and correlated with clinicopathological features, and patient outcome. Results Nuclear RXRG expression was significantly associated with smaller tumour size (p = 0.036), lower grade (p < 0.001), lobular histology (p = 0.016), lower Nottingham Prognostic Index (p = 0.04) and longer breast cancer-specific survival (p < 0.001), and longer time to distant metastasis (p = 0.002). RXRG expression showed positive association with oestrogen receptor (ER)-related biomarkers: GATA3, FOXA1, STAT3 and MED7 (all p < 0.001) and a negative correlation with the Ki67 proliferation marker. Multivariate analysis demonstrated RXRG protein as an independent predictor of longer breast cancer-specific survival and distant metastasis-free survival. In the external validation cohorts, RXRG expression was associated with improved patients’ outcome (p = 0.025). In ER-positive tumours, high expression of RXRG was associated with better patient outcome regardless of adjuvant systemic therapy. ER signalling pathway was the top predicted master regulator of RXRG protein expression (p = 0.005). Conclusion This study provides evidence for the prognostic value of RXRG in breast cancer particularly the ER-positive tumours.

Cytoplasmic Localization of RXRα Determines Outcome in Breast Cancer

“…No studies have so far examined the prognostic value of the intracellular expression of RXRα in BC subcohorts. Previously, Joseph et al reported that high-nuclear retinoid X receptor gamma (RXRG) expression in ER-positive BC tissue samples was associated with a better prognostic impact [69]. This is consistent with previous reports indicating a positive prognostic value of nuclear RXRG in ER-and PR-positive BC [70].…”

“…Furthermore, both the activation of RXR and the higher expression of RXR in epithelial ovarian cancer have been found to foster pro-apoptotic mechanisms [72]. In BC cells and other tumor entities, RXR is able to execute responses such as cell proliferation, cellular differentiation and programmed cell death [45,69]. Consequently, RXR is a potential therapeutic target in breast cancer cell lines [44,45].…”

The Prognostic Impact of Retinoid X Receptor and Thyroid Hormone Receptor alpha in Unifocal vs. Multifocal/Multicentric Breast Cancer

“…The nuclear receptor RXR has been proven to modulate cellular differentiation and apoptosis in different tumor entities [ 49 ]. RXR and its heterodimers regulate the function of myeloid cells, link cellular metabolism, and show a profound effect on immune function [ 50 , 51 ].…”

20(S)‐Protopanaxadiol inhibits epithelial‐mesenchymal transition by promoting retinoid X receptor alpha in human colorectal carcinoma cells

“…It also reported that RXRα was bound by berberine to suppressed β‐catenin in colon cancer 29 30 although the other two isoforms of RXR, β and γ, also have some anti‐tumour effects 31‐36 . However, studies have shown that deficiencies in the α subtype have been shown to have a more detrimental impact on health compared with the other isoforms 37‐39 .…”