Targeting the IL-6/STAT3 Signalling Cascade to Reverse Tamoxifen Resistance in Estrogen Receptor Positive Breast Cancer

SIMPLE SUMMARY: This study identifies the molecular mechanisms through which BQ323636.1 can enhance IL-6 and IL-6R expression, which leads to the activation of STAT3 and the development of tamoxifen resistance in ER+ breast cancer. We demonstrated a statistically significant association of IL-6R with tamoxifen resistance; patients with high IL-6R expression had poorer survival outcome. In vitro and in vivo studies confirmed that targeting IL-6R with Tocilizumab reduced tamoxifen resistance, providing the basis for potential use for disease management ABSTRACT: Breast cancer is the most common female cancer. About 70% of breast cancer patients are estrogen receptor α (ERα) positive (ER+) with tamoxifen being the most commonly used anti-endocrine therapy. However, up to 50% of patients who receive tamoxifen suffer recurrence. We previously identified BQ323636.1 (BQ), a novel splice variant of NCOR2, can robustly predict tamoxifen resistance in ER+ primary breast cancer. Here we show that BQ can enhance IL-6/STAT3 signalling. We demonstrated that through interfering with NCOR2 suppressive activity, BQ favours the binding of ER to IL-6 promoter and the binding of NF-ĸB to IL-6 receptor (IL-6R) promoter, leading to the up-regulation of both IL-6 and IL-6R and thus the activation of STAT3. Knockdown of IL-6R could compromise tamoxifen resistance mediated by BQ. Furthermore, Tocilizumab (TCZ), an antibody that binds to IL-6R, could effectively reverse tamoxifen resistance both in vitro and in vivo. Analysis of clinical breast cancer samples confirmed that IL-6R expression was significantly associated with BQ expression and tamoxifen resistance in primary breast cancer, with high IL-6R expression correlating with poorer survival. Multivariate Cox-regression analysis confirmed that high IL-6R expression remained significantly associated with poor overall as well as disease-specific survival in ER+ breast cancer.