title: Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins.
abstract: The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA-BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75% (p < 0.05). The specific rescue of prenylation using farnesyl pyrophosphate or geranylgeranyl pyrophosphate revealed that these effects were mediated by suppressed geranylgeranylation rather than by suppressed farnesylation. Moreover, combining low concentrations of statins (1 µM atorvastatin or 0.25 µM simvastatin) and zoledronic acid at low concentrations resulted in an at least 50% reversal of breast cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p < 0.05). Finally, the intratumoral injection of atorvastatin and zoledronic acid in as subcutaneous MDA-MB-231 mouse model reduced the serum level of human DKK-1 by 25% compared to untreated mice. Hence our study reveals that a sequential mevalonate pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation.
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
authors.forename: Andy
authors.initials: A
authors.lastname: Göbel
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Browne
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Thiele
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.|Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany. Tilman.Rachner@uniklinikum-dresden.de.
authors.forename: Tilman D
authors.initials: TD
authors.lastname: Rachner
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000069059:Atorvastatin / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008819:Mice, Nude; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D000068718:Rosuvastatin Calcium / Q000008:administration & dosage; D019821:Simvastatin / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: C501126:DKK1 protein, human; D004164:Diphosphonates; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D000077211:Zoledronic Acid; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin; D019821:Simvastatin; D008798:Mevalonic Acid
keywords: Breast cancer; Dickkopf-1; Mevalonate pathway; Osteoblasts; Statins; Zoledronic acid