Increased Expression of Interleukin-1 Receptor Characterizes Anti-estrogen-Resistant ALDH+ Breast Cancer Stem Cells

• Published in: Stem cell reports Vol. 15; no. 2; pp. 307 - 316
• Main Authors: Sarmiento-Castro, Aida, Caamaño-Gutiérrez, Eva, Sims, Andrew H., Hull, Nathan J., James, Mark I., Santiago-Gómez, Angélica, Eyre, Rachel, Clark, Christopher, Brown, Martha E., Brooks, Michael D., Wicha, Max S., Howell, Sacha J., Clarke, Robert B., Simões, Bruno M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.08.2020; Elsevier
• Subjects: ALDH+ cells; anti-estrogens; breast cancer stem cells; dormancy; IL1R1; anti-estrogens; breast cancer stem cells; IL1R1; dormancy; ALDH+ cells; ALDH(+) cells
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2020.06.020

Estrogen-receptor-positive breast tumors are treated with anti-estrogen (AE) therapies but frequently develop resistance. Cancer stem cells (CSCs) with high aldehyde dehydrogenase activity (ALDH+ cells) are enriched following AE treatment. Here, we show that the interleukin-1β (IL-1β) signaling pathway is activated in ALDH+ cells, and data from single cells reveals that AE treatment selects for IL-1 receptor (IL1R1)-expressing ALDH+ cells. Importantly, CSC activity is reduced by an IL1R1 inhibitor in AE-resistant models. Moreover, IL1R1 expression is increased in the tumors of patients treated with AE therapy and predicts treatment failure. Single-cell gene expression analysis revealed that at least two subpopulations exist within the ALDH+ population, one proliferative and one quiescent. Following AE therapy the quiescent population is expanded, which suggests CSC dormancy as an adaptive strategy that facilitates treatment resistance. Targeting of ALDH+IL1R1+ cells merits testing as a strategy to combat AE resistance in patients with residual disease. •Anti-estrogen-resistant ALDH+ cells have increased CSC activity in ER+ tumors•The IL1R1-expressing ALDH+ CSC population expands after anti-estrogen treatment•IL1R1 expression predicts anti-estrogen treatment failure•Targeting of ALDH+IL1R1+ cells reverses anti-estrogen resistance In this study, Simões, Clarke and colleagues show that anti-estrogen treatments select for ALDH+ breast cancer stem cells expressing IL1R1, which can be targeted by a specific inhibitor. Increased expression of IL1R1 is observed in the tumors of patients treated with anti-estrogen therapy, suggesting that targeting of ALDH+IL1R1+ cells will help combat therapy resistance.