期刊
CANCERS
卷 13, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/cancers13071511
关键词
breast cancer; interleukin-6; interleukin-6 receptor; tamoxifen resistance; Tocilizumab; STAT3
类别
资金
- Health and Medical Research Fund, HKSAR [06171696, 06171916]
- Committee on Research and Conference Grants from the University of Hong Kong [201811159118, 201910160022, 201910159174]
This study identifies the molecular mechanisms through which BQ323636.1 enhances IL-6/STAT3 signaling, promoting tamoxifen resistance in ER+ breast cancer. High IL-6R expression is significantly associated with tamoxifen resistance, and targeting IL-6R with Tocilizumab can reverse this resistance. Analysis of clinical samples confirmed the correlation between IL-6R expression, BQ expression, and tamoxifen resistance in primary breast cancer. High IL-6R expression is linked to poorer survival outcomes in ER+ 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 Breast cancer is the most common female cancer. About 70% of breast cancer patients are estrogen receptor alpha (ER alpha) 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-kappa B 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.
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