HIF-1–regulated expression of calreticulin promotes breast tumorigenesis and progression through Wnt/beta-catenin pathway activation
Menée in vitro et à l'aide d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel l'expression de la calréticuline, régulée par le facteur de transcription HIF-1, favorise la tumorigenèse mammaire et la progression de la maladie via l'activation de la voie de signalisation Wnt/bêta-caténine
Breast cancer stem cells (BCSCs) have the property of infinite self-renewal. When these cells divide, they give rise to one BCSC and one transient amplifying cell that can rapidly proliferate but only for a limited number of cell divisions. Only BCSCs can give rise to secondary (recurrent and/or metastatic) tumors. It is believed that breast cancer recurrence is due to the survival of a small number of BCSCs. Because the BCSCs represent a very small minority of cells within the primary tumor, their unique characteristics may not be detected by bulk tumor analyses. BCSCs are often located within regions of intratumoral hypoxia, and hypoxia-inducible factors activate the transcription of genes that promote BCSC specification and/or maintenance.Calreticulin (CALR) is a multifunctional protein that participates in various cellular processes, which include calcium homeostasis, cell adhesion, protein folding, and cancer progression. However, the role of CALR in breast cancer (BC) is unclear. Here, we report that CALR is overexpressed in BC compared with normal tissue, and its expression is correlated with patient mortality and stemness indices. CALR expression was increased in mammosphere cultures, CD24−CD44+ cells, and aldehyde dehydrogenase–expressing cells, which are enriched for breast cancer stem cells (BCSCs). Additionally, CALR knockdown led to BCSC depletion, which impaired tumor initiation and metastasis and enhanced chemosensitivity in vivo. Chromatin immunoprecipitation and reporter assays revealed that hypoxia-inducible factor 1 (HIF-1) directly activated CALR transcription in hypoxic BC cells. CALR expression was correlated with Wnt/β-catenin pathway activation, and an activator of Wnt/β-catenin signaling abrogated the inhibitory effect of CALR knockdown on mammosphere formation. Taken together, our results demonstrate that CALR facilitates BC progression by promoting the BCSC phenotype through Wnt/β-catenin signaling in an HIF-1–dependent manner and suggest that CALR may represent a target for BC therapy.