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.

Fig. 1

Western blot and immunohistochemical expression of RXRG in breast cancer. a Western blotting results for RXRG expression in MCF-7 and MDA-MB231 breast cancer cell lines using rabbit polyclonal antibody (Abcam, ab15518). Green and red bands represent RXRG and the house-keeping Beta-Actin, respectively. RXRG protein expression in breast cancer tissue microarrays cores. b Negative/no staining c showing low expression and d showing high immunoreactivity. Images are at x40 magnification

Fig. 2

Kaplan–Meier plot for the association of RXRG nuclear expression. Whole series: a Breast cancer-specific survival, b distant metastasis-free survival. In ER-positive tumours. c Breast cancer-specific survival, d distant metastasis-free survival. Kaplan–Meier analysis of breast cancer-specific survival showing the impact of treatment on RXRG nuclear protein expression in ER-positive cohort; e in patients who did receive hormone therapy f in patients that did not receive hormone therapy g in patients who did receive chemotherapy and h in patients who did not receive chemotherapy with significance determined using the log-rank test