Dorsomorphin: A novel inhibitor of Dickkopf-1 in breast cancer

Abstract

Advanced stages of breast cancer are frequently complicated by bone metastases which cause substantial cancer-related morbidity and mortality. The Wnt-signaling antagonist Dickkopf-1 (DKK-1) has emerged as a crucial factor in the development and progression of osteolytic bone metastases. Although several signaling pathways have been implicated in promoting DKK-1 production in breast cancer cells, pharmacological interventions that interfere with tumor DKK-1 synthesis still remain scarce. In the current study, using an unbiased approach, we identified the small molecule Dorsomorphin as a potent suppressor of DKK-1 in several breast cancer cell lines (MDA-MB-231, MDA-Bone, MDA-MET and MCF7, respectively). Here, Dorsomorphin suppressed DKK-1 mRNA and protein production by 70 and 90%, respectively (p <0.001). Whereas bone morphogenic protein (BMP)- and AMP activated protein kinase (AMPK)-signaling are two well-established targets of Dorsomorphin, we show that neither pathway is essentially involved in facilitating its inhibitory effects on DKK-1. In summary, we identified Dorsomorphin as a potent pharmacological inhibitor of DKK-1 production in breast cancer cells. Whether Dorsomorphin reflects a valuable therapeutic agent in breast cancer warrants further investigations.

Keywords: Bone metastases; Breast cancer; Dickkopf-1; Dorsomorphin.