title: P38 regulates the Wnt inhibitor Dickkopf-1 in breast cancer.
abstract: Dickkopf-1 (DKK-1) is an inhibitor of canonical Wnt signalling and has been associated with the progression of osteolytic bone metastases by impairing osteoblast activity. In addition, there is growing evidence supporting a direct anti-tumour effect of DKK-1. The p38 mitogen-activated protein kinase (MAPK) regulates intracellular responses that have been linked to cell cycle, apoptosis and tumorigenesis. P38 inhibitors are currently under clinical evaluation for the treatment of malignancies. However, the influence of p38 on DKK-1 in breast cancer remains elusive. In this work, we show that p38 inhibition using SB202190 or LY2228820 potently suppressed DKK-1 expression by MDA-231 and MCF-7 breast cancer cell lines as well melanoma derived MDA-435 cells. Vice versa, activation of p38 signalling by anisomycin induced DKK-1 expression. Immunohistochemical analysis of DKK-1 expression in 97 breast cancer samples revealed that high expression of p38 was associated with a higher expression of DKK-1 compared to tumours with low p38 expression. In conclusion, these results support a role of p38 in the regulation of DKK-1 in osteolytic tumours and warrant further research on the potential of p38 inhibition for the treatment of malignant bone disease.
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany. Electronic address: tilman.rachner@uniklinikum-dresden.de.
authors.forename: Tilman D
authors.initials: TD
authors.lastname: Rachner
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Andy
authors.initials: A
authors.lastname: Göbel
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Browne
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Josefa
authors.initials: J
authors.lastname: Hötzel
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; DFG Research Center and Cluster of Excellence for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
mesh_terms: D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C501126:DKK1 protein, human; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051153:Wnt Proteins; C580958:ralimetinib; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
keywords: Breast cancer; Dickkopf-1; p38