• 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.; et al. (2020)
      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.