POU1F1 induces cancer stem cell-like traits in breast cancer cells by IL-6/JAK2/STAT3 activation and enrichment of ALDH

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.