The medical mushroom Ganoderma lucidum (Reishi), a traditional Chinese medicine, has exhibited a promising anti-cancer effect. However, the molecular mechanism of its action on cancer cells remains unclear. Aberrant activation of Wnt/beta-catenin signaling pathway is the cause of many types of cancer, including breast cancer. Here we investigated the effect of Reishi on Wnt/beta-catenin signaling pathway and elucidated the molecular mechanism of its function in inhibiting breast cancer cells. We found that Reishi blocked Wnt/beta-catenin signaling through inhibiting the phosphorylation of Wnt co-receptor LRP6. In human (MDA-MB-231) and mouse (4T1) breast cancer cell lines, Reishi significantly decreased the phosphorylation of LRP6 and suppressed Wnt3a-activated Wnt target gene Axing expression. Administration of Reishi inhibited Wnt-induced hyper-proliferation of breast cancer cells and MDA-MB-231 cell migration. Our results provide evidence that Reishi suppresses breast cancer cell growth and migration through inhibiting Wnt/beta-catenin signaling, indicating that Reishi may be a potential natural inhibitor for breast cancer. (C) 2017 Elsevier Inc. All rights reserved.