The NFκB pathway promotes endocrine therapy tolerance through activation of integrated stress response in ER positive breast cancer

While estrogen receptor positive breast tumors generally respond well to endocrine therapy (ET), up to 40% of patients will experience relapse, either while on endocrine therapy or after ET is completed. We have previously shown that the selective pressure of tamoxifen activates the pro-survival NFkB pathway in patient tumors, breast cancer cell lines, and breast cancer xenograft tumors, and that this activation allows for survival of a population of ET-tolerant cells, which can contribute to relapse after ET withdrawal. Here, we utilized single cell RNA-sequencing to characterize survival pathways in NFkB+, ET-tolerant cells and identified activation of the integrated stress response as a critical survival mechanism. Moreover, we found key players in this pathway are regulated by ET in patient derived organoids. In addition, we developed an ET-tolerant gene signature that can be found in metastatic cell populations and that predicts poor outcome to ET. Our findings suggest that co-targeting of ER and key players in the integrated stress response may be a viable therapeutic strategy to eliminate cells that survive the selective pressure of ET. scRNA-seq (OneCellBio)

雌激素受体阳性乳腺肿瘤通常对内分泌治疗（endocrine therapy, ET）应答良好，但仍有高达40%的患者会出现复发，无论复发发生在内分泌治疗期间，还是完成内分泌治疗之后。我们此前已证实，他莫昔芬的选择压力可在患者肿瘤、乳腺癌细胞系以及乳腺癌异种移植瘤中激活促存活的核因子κB（NFκB）通路，且该通路的激活可使内分泌治疗耐受细胞群得以存活，此类细胞可在内分泌治疗停药后促成肿瘤复发。本研究利用单细胞RNA测序（single cell RNA-sequencing, scRNA-seq）对核因子κB阳性、内分泌治疗耐受细胞的存活通路进行了系统表征，并确定整合应激反应的激活是其中关键的存活机制。此外，我们发现该通路中的关键调控因子可在患者来源类器官中受到内分泌治疗的调控。除此之外，我们还开发了一个内分泌治疗耐受基因特征，该特征可在转移细胞群中被检测到，并可用于预测内分泌治疗的不良预后。本研究结果提示，同时靶向雌激素受体与整合应激反应中的关键调控因子，或可成为一种可行的治疗策略，以清除在内分泌治疗选择压力下存活的肿瘤细胞。scRNA-seq（OneCellBio）