Targeting the IL-6/STAT3 Signalling Cascade to Reverse Tamoxifen Resistance in Estrogen Receptor Positive Breast Cancer
Ho Tsoi, Ellen P.S. Man, Ka Man Chau, US Khoo
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.