A Sox2–Sox9 signalling axis maintains human breast luminal progenitor and breast cancer stem cells

Increased cancer stem cell content during development of resistance to tamoxifen in breast cancer is driven by multiplesignals, including Sox2-dependent activation of Wnt signalling. Here, we show that Sox2 increases and estrogen reduces theexpression of the transcription factor Sox9. Gain and loss of function assays indicate that Sox9 is implicated in themaintenance of human breast luminal progenitor cells. CRISPR/Cas knockout of Sox9 reduces growth of tamoxifen-resistantbreast tumours in vivo. Mechanistically, Sox9 acts downstream of Sox2 to control luminal progenitor cell content and isrequired for expression of the cancer stem cell marker ALDH1A3 and Wnt signalling activity. Sox9 is elevated in breastcancer patients after endocrine therapy failure. This new regulatory axis highlights the relevance of SOX family transcriptionfactors as potential therapeutic targets in breast cancer.