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

Aida Sarmiento-Castro,Nathan J Hull,Eva Caamaño-Gutiérrez,Robert B Clarke,Bruno M Simões,Rachel Eyre,Christopher Clark,Andrew H Sims,Sacha J Howell,Mark I James,Martha E Brown,Max S Wicha,Angélica Santiago-Gómez,Michael D Brooks

doi:10.1016/j.stemcr.2020.06.020

Abstract

SummaryEstrogen-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

Following AE therapy the vast majority of Aldehyde dehydrogenase (ALDH)+ cells show high interleukin-1 receptor type 1 (IL1R1) gene expression levels (Figures 3B and S3B). These results reveal the existence of cellular diversity within the ALDH+ population that can be unraveled by single-cell gene expression profiling, and highlight IL1R1 as an important gene in AE-resistant breast CSCs (BCSCs)
We reported that ALDH+ cells are resistant to AE therapy and that high ALDH1 expression predicts resistance in women treated with tamoxifen (Simoes et al, 2015)
ALDH1A1 and ALDH1A3 isoforms are both reported to be predictive biomarkers of poor clinical outcome in Breast cancer (BC) (Liu et al, 2014; Marcato et al, 2011), and we found them to be the most highly increased among 18 ALDH isoforms detected in metastatic patient-derived ALDH+ BC cells

Summary

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. We show that the interleukin-1b (IL-1b) 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. 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

RESULTS

Findings

DISCUSSION

EXPERIMENTAL PROCEDURES