Identification of a novel ER-NF?B driven stem-like cell population associated with poor outcome of ER+ breast cancer patients

Up to 40% of patients with Estrogen Receptor positive (ER+) breast cancer experience relapse. Breast cancer stem cells (BCSCs) are known to be involved in therapy resistance, relapse, and development of more aggressive and metastatic tumors. Therefore, there is an urgent need to identify genes/pathways that drive stem-like cell properties in ER+ breast tumors. Using single-cell RNA sequencing and bioinformatic approaches, with additional follow-up studies, we identified a unique quiescent stem-like cell population that is driven by ER and NFkB in multiple ER+ breast cancer models. Moreover, a gene signature derived from this stem-like population is expressed in endocrine therapy-resistant and metastatic cell populations and predictive of poor patient outcome. These findings indicate a novel role for ER and NFkB crosstalk in BCSCs biology and understanding the mechanism by which these pathways promote stem properties may be exploited to improve outcomes for ER+ breast cancer patients at risk of relapse. Overall design: scRNA-seq (10XGenomics)

约40%的雌激素受体阳性（Estrogen Receptor positive, ER+）乳腺癌患者会出现疾病复发。已知乳腺癌干细胞（Breast cancer stem cells, BCSCs）与治疗耐药、疾病复发以及高侵袭性、转移性肿瘤的发生发展密切相关。因此，亟需筛选出可驱动ER+乳腺肿瘤中干细胞样细胞特性的基因或信号通路。本研究通过单细胞RNA测序与生物信息学分析，并辅以后续验证实验，在多种ER+乳腺癌模型中鉴定出一类由ER与NFkB驱动的独特静息态干细胞样细胞群。此外，从该干细胞样细胞群中提取的基因特征可在内分泌治疗耐药及转移性细胞群中表达，且可预示患者不良预后。上述研究结果揭示了ER与NFkB串扰在BCSCs生物学中的全新作用，阐明这两条通路促进干细胞特性的具体机制，或可用于改善存在复发风险的ER+乳腺癌患者的临床结局。实验设计概况：scRNA-seq（10XGenomics）