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Increased expression of interleukin-1 receptor characterizes anti-estrogen-resistant ALDH(+) breast cancer stem cells
Sarmiento-Castro, Aida Caamaño-Gutiérrez, E Sims, Andrew H Hull, N J James, M Santiago-Gómez, Angélica Eyre, Rachel Clark, Christopher Brown, M. E. Brooks, M. D.
Sarmiento-Castro, Aida
Caamaño-Gutiérrez, E
Sims, Andrew H
Hull, N J
James, M
Santiago-Gómez, Angélica
Eyre, Rachel
Clark, Christopher
Brown, M. E.
Brooks, M. D.
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Abstract
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-1? (IL-1?) 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.
Keywords: ALDH(+) cells; IL1R1; anti-estrogens; breast cancer stem cells; dormancy.
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Date
2020
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Sarmiento-Castro A, Caamano-Gutierrez E, Sims AH, Hull NJ, James MI, Santiago-Gomez A, et al. Increased Expression of Interleukin-1 Receptor Characterizes Anti-estrogen-Resistant ALDH(+) Breast Cancer Stem Cells. Stem Cell Reports. 2020;15(2):307-16.