Increased Expression of Interleukin-1 Receptor Characterizes Anti-estrogen-Resistant ALDH
| Autor: | Aida, Sarmiento-Castro, Eva, Caamaño-Gutiérrez, Andrew H, Sims, Nathan J, Hull, Mark I, James, Angélica, Santiago-Gómez, Rachel, Eyre, Christopher, Clark, Martha E, Brown, Michael D, Brooks, Max S, Wicha, Sacha J, Howell, Robert B, Clarke, Bruno M, Simões |
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| Rok vydání: | 2019 |
| Předmět: |
breast cancer stem cells
dormancy Gene Expression Profiling ALDH+ cells Estrogen Antagonists Receptors Interleukin-1 anti-estrogens Breast Neoplasms Aldehyde Dehydrogenase 1 Family Gene Expression Regulation Neoplastic IL1R1 Drug Resistance Neoplasm Cell Line Tumor Report Neoplastic Stem Cells Humans Female Neoplasm Metastasis Single-Cell Analysis Transcriptome |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| Popis: | Summary 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. Highlights • 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. |
| Databáze: | OpenAIRE |
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