Dorsomorphin reverses the mesenchymal phenotype of breast cancer initiating cells by inhibition of bone morphogenetic protein signaling

• Published in: Cellular signalling 2014-02, Vol.26 (2), p.352-362
• Main Authors: Garulli, Chiara, Kalogris, Cristina, Pietrella, Lucia, Bartolacci, Caterina, Andreani, Cristina, Falconi, Maurizio, Marchini, Cristina, Amici, Augusto
• Format: Article
• Language: English
• Subjects: Animals; Bone Morphogenetic Protein 4 - pharmacology; Bone Morphogenetic Protein Receptors, Type I - metabolism; Bone Morphogenetic Protein Receptors, Type II - metabolism; Bone Morphogenetic Proteins - metabolism; Bone morphogenic proteins; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Dorsomorphin; EMT (epithelial–mesenchymal transition); Epithelial-Mesenchymal Transition - drug effects; Female; Gene Expression Regulation - drug effects; Humans; Inhibitor of Differentiation Protein 1 - metabolism; Mesenchymal cancer stem cells; Mice; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Phenotype; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrimidines - chemistry; Pyrimidines - pharmacology; Signal Transduction - drug effects
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2013.11.022

Increasing evidence supports the theory that tumor growth, homeostasis, and recurrence are dependent on a small subset of cells with stem cell properties, redefined cancer initiating cells (CICs) or cancer stem cells. Bone morphogenetic proteins (BMPs) are involved in cell-fate specification during embryogenesis, in the maintenance of developmental potency in 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 displaying properties of CICs, we investigated the role of BMPs in the control of breast cancer cell plasticity. We showed that an autocrine activation of BMP signaling is crucial for the maintenance of mesenchymal stem cell phenotype and tumorigenic potential of A17 cells. Pharmacological inhibition of BMP signaling cascade by Dorsomorphin resulted in the acquisition of epithelial-like traits by A17 cells, including expression of Citokeratin-18 and E-cadherin, through downregulation of Snail and Slug transcriptional factors and Cyclooxygenase-2 (COX2) expression, and in the loss of their stem-features and self-renewal ability. This phenotypic switch compromised A17 cell motility, invasiveness and in vitro tumor growth. These results reveal that BMPs are key molecules at the crossroad between stemness and cancer. •BMP signaling promotes proliferation, migration and invasion of breast CICs.•Inhibition of BMP signaling by Dorsomorphin induces MET in breast CICs.•Dorsomorphin causes loss of stem-like traits in breast CICs.•Dorsomorphin depletes the tumorigenic potential of breast CICs.•BMP/Cyclooxygenase-2 axis controls the mesenchymal plasticity of breast CICs.