BMP4: the crossroad between stemness and cancer

Increasing evidence supports the theory that tumor growth, maintenance, and recurrence are dependent on a small subset of cells with stem properties, redefined cancer initiating cells (CIC) or cancer stem cells (CSC). Bone morphogenetic proteins (BMPs)are extracellular signalling molecules, member of the transforming growth factor β (TGF†β)superfamily. These factors control various cellular processes, such as proliferation, differentiation, apoptosis and migration. Moreover they are involved in cell†fate specification during embryogenesis, in the maintenance of developmental potency in embryonic and adult stem cells and may contribute to sustain CIC populations in breast carcinoma. Using the mouse A17 cell model previously related to mesenchymal cancer stem cells and basal-­like breast cancer, we investigated the role of BMPs in the control of breast cancer cell plasticity. We showed an autocrine activation of BMPs signaling pathway in A17 cells that seems to be crucial for the maintenance of their mesenchymal and stem-†like phenotype. Pharmacological inhibition of BMPs signaling cascade by Dorsomorphin, a small molecule inhibitor of BMP Type I Receptor kinases, induced loss of A17s mesenchymal features, by downregulating Snail and Slug transcriptional factors and COX2 expression, resulting in the acquirement of epithelial­†like traits. Dorsomorphin treatment led also to a decrease of stem cell markers expression, resulting in the loss of self­†renewal ability. This phenotypic switch compromised A17 cells motility, invasion ability and in vitro tumor growth through inhibition of cell cycle progression. Transient transfection with a pool of four different synthetic siRNA molecules targeting specifically BMP4 gave similar results supporting the specificity of pharmacological treatment evidencing BMP4 crucial role. Taken together these results reveal that BMPs family, and in particular BMP4, can be considered the key molecules at the crossroad between stemness and cancer.