Abstract
Increased cancer stem cell content during development of resistance to tamoxifen in breast cancer is driven by multiple signals, including Sox2-dependent activation of Wnt signalling. Here, we show that Sox2 increases and estrogen reduces the expression of the transcription factor Sox9. Gain and loss of function assays indicate that Sox9 is implicated in the maintenance of human breast luminal progenitor cells. CRISPR/Cas knockout of Sox9 reduces growth of tamoxifen-resistant breast tumours in vivo. Mechanistically, Sox9 acts downstream of Sox2 to control luminal progenitor cell content and is required for expression of the cancer stem cell marker ALDH1A3 and Wnt signalling activity. Sox9 is elevated in breast cancer patients after endocrine therapy failure. This new regulatory axis highlights the relevance of SOX family transcription factors as potential therapeutic targets in breast cancer.
Highlights
Breast cancer is a very heterogeneous disease
Breast epithelial cells were isolated from reduction mammoplasties and Fluorescence activated cell sorting (FACS) sorted according to different phenotypes
Western blot (Fig. 1a) and immunofluorescence (Fig. 1b) analyses of FACS sorted cells from five reduction mammoplasties showed that Sox9 is predominantly expressed by the double-positive CD49f +EpCAM+ luminal progenitor cell subset and, to a lesser extent, by CD49f−EpCAM+ luminal cells
Summary
Breast cancer is a very heterogeneous disease. Analysis of the gene expression profiles of breast carcinomas has revealed the existence of various tumour subtypes with clinical implications [1]. Further studies, including the integrated analysis of copy number and gene expression, have revealed the presence of a novel molecular. These authors contributed : Iskander Aurrekoetxea-Rodríguez, Bruno M. Sox has been shown to be a key regulator of mammary gland development and stem/progenitor cell maintenance [18] and, in breast cancer patients, high-Sox expression has been associated with estrogen receptor (ER)-negative tumours, significantly shorter overall survival and poor survival [19]. Our observations support a model in which Sox is required for the maintenance of luminal progenitors in the human breast and for Wnt signalling in tamoxifenresistant breast cancer cells
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