The FBXW7 tumor suppressor inhibits breast cancer proliferation and promotes apoptosis by targeting MTDH for degradation.

Metadherin (MTDH) is an oncoprotein and is expressed at high levels in a wide variety of human carcinomas, which represents an important genetic determinant and regulates multiple events in tumorigenesis. MTDH promotes breast cancer cell proliferation and tumorigenesis through the activation of numerous signaling pathways. Currently, the mecha- nism regulating MTDH expression is poorly understood. Here we identified that FBXW7, a component of E3 ubiquitin ligase, targets MTDH for ubiquitin-mediated degradation. Forced overexpression of FBXW7 could decrease the level of MTDH protein, and inhibition of endogenous FBXW7 expression remarkably increases the MTDH protein abundance. More importantly, overexpression of FBXW7 could lead to proliferation arrest and apoptosis in breast cancer cells through targeting MTDH degradation. These data suggest that FBXW7, a tumor suppressor, inhibits breast cancer cell prolifera- tion and promotes apoptosis at least partially through targeting MTDH for proteolysis. This new regulatory mechanism of MTDH by FBXW7 represents a new pathway for malignant phenotype turnover in human breast cancer.