Abstract
Breast cancer stem cells (BCSCs) have been proposed as the cause of resistance to conventional treatments and of breast cancer recurrence and metastasis. This study provides compelling evidence for the role of the transcription factor POU1F1 in the increase of BCSC-like. Using POU1F1-overexpressing and knock-down breast cancer cell lines, as well as immunodeficient mouse models, our data demonstrate that POU1F1 induces a BCSC-like phenotype in breast tumor cells by deregulating markers such as CD24, CD44, CD133, and ALDH. These phenotypic modifications correlate with functional changes, i.e., increased clonogenicity, mammosphere formation, and glycolysis. In addition, we found that a subpopulation of MCF-7 cells with overexpression of POU1F1 and elevated ALDH expression exhibits both a high tumor-initiating capacity and increased resistance to chemotherapy and radiotherapy treatments. Mechanistically, these features are mediated by POU1F1 activation of the IL-6/JAK2/STAT3 pathway and up-regulation of ALDH. Janus kinase inhibitors and monoclonal anti-IL6 receptor antibodies significantly decrease ALDH expression, colony, and mammosphere formation, suggesting possible use of pharmacological inhibitors of the IL-6/JAK2/STAT3 pathway in breast tumors with elevated POU1F1 levels.
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Data availability
Raw and processed data for sequencing studies are available from NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession numbers GSE287812 (MCF-7 cells), GSE287732 (HMEC), with and without POU1F1 overexpression (POU1F1) (RNA-seq). All other data will be available from the authors upon request.
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Acknowledgements
We thank Dr. A. Martinez-Ordoñez for his valuable suggestions and critical reading of the manuscript. This study was supported by FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (PID2021-127394OB-100) and the EU MSCA-DC eRaDicate-101119427 to R.P.-F. L.A.C. and S.R.-G. are fellows of the Xunta de Galicia Predoctoral Scholarship 2020. M.G. is a Marie-Curie PhD student (101119427).
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Leandro Avila: Methodology, investigation, validation, formal analysis, data curation, and writing. Samuel Seoane: Methodology, investigation, formal analysis, and data curation. Sandra Rodriguez-Gonzalez: Methodology and formal analysis. Magda Gois: Methodology, investigation, and formal analysis. Maria Efigenia Arias: Methodology, investigation, and formal analysis. David Martinez-Delgado: Data curation. Noemi Lado: Data curation. Tomas Garcia-Caballero: Data curation, methodology, and investigation. Pablo Aguiar: Methodology and investigation. Roman Perez-Fernandez: Visualization, validation, supervision, resources, project administration, methodology, funding acquisition, formal analysis, data curation, conceptualization, and writing & editing.
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Avila, L., Seoane, S., Rodriguez-Gonzalez, S. et al. POU1F1 induces cancer stem cell-like traits in breast cancer cells by IL-6/JAK2/STAT3 activation and enrichment of ALDH. npj Breast Cancer (2026). https://doi.org/10.1038/s41523-026-00929-w
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DOI: https://doi.org/10.1038/s41523-026-00929-w
