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Background: Up to 40% of patients with estrogen receptor-positive (ER+) breast cancer experience relapse. This can be attributed to breast cancer stem cells (BCSCs), which are known to be involved in therapy resistance, relapse, and metastasis. Therefore, there is an urgent need to identify genes/pathways that drive stem-like cell properties in ER+ breast tumors., Methods: Using single-cell RNA sequencing and various bioinformatics approaches, we identified a unique stem-like population and established its clinical relevance. With follow-up studies, we validated our bioinformatics findings and confirmed the role of ER and NFĸB in the promotion of stem-like properties in breast cancer cell lines and patient-derived models., Results: We identified a novel quiescent stem-like cell population that is driven by ER and NFĸB in multiple ER+ breast cancer models. Moreover, we found that a gene signature derived from this stem-like population is expressed in primary ER+ breast tumors, endocrine therapy-resistant and metastatic cell populations and predictive of poor patient outcome., Conclusions: These findings indicate a novel role for ER and NFĸB crosstalk in BCSCs biology and understanding the mechanism by which these pathways promote stem properties can be exploited to improve outcomes for ER+ breast cancer patients at risk of relapse., (© 2022. The Author(s).)

Background: While estrogen receptor (ER) 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 previously demonstrated that the selective pressure of tamoxifen activates the NFκB pathway in ER + patient tumors, breast cancer cell lines, and breast cancer xenograft tumors, and that this activation allows for survival of a subpopulation of NFκB + cells that contribute to cell regrowth and tumor relapse after ET withdrawal. However, the mechanisms contributing to the expansion of an NFκB + cell population on ET are unknown., Methods: Here, we utilized single-cell RNA sequencing and bioinformatics approaches to characterize the NFκB + cell population and its clinical relevance. Follow-up studies were conducted to validate our findings and assess the function of the integrated stress response pathway in breast cancer cell lines and patient-derived models., Results: We found that the NFκB + population that arises in response to ET is a preexisting population is enriched under the selective pressure of ET. Based on the preexisting NFκB + cell population, we developed a gene signature and found that it is predictive of tumor relapse when expressed in primary ER + tumors and is retained in metastatic cell populations. Moreover, we identified that the integrated stress response (ISR), as indicated by increased phosphorylation of eIF2α, occurs in response to ET and contributes to clonogenic growth under the selective pressure of ET., Conclusions: Taken together, our findings suggest that a cell population with active NFκB and ISR signaling can survive and expand under the selective pressure of ET and that targeting this population may be a viable therapeutic strategy to improve patient outcome by eliminating cells that survive ET. Understanding the mechanisms by which breast cancer cells survive the selective pressure of ET may improve relapse rates and overall outcome for patients with ER + breast tumors., (© 2022. The Author(s).)