The CRL7^FBXW8 Complex Controls the Mammary Stem Cell Compartment through Regulation of NUMB Levels.

ABSTRACT: NUMB is a tumor suppressor gene that functions by inhibiting the action of the NOTCH proto-oncogene and enhancing the levels and activity of the tumor suppressor protein p53. In breast cancer (BC), NUMB loss of function (LOF), mediated by various molecular mechanisms, is a frequent and causal event. Herein, it is established that loss of NUMB protein, resulting from protein hyper-degradation, is the prevalent mechanism of NUMB LOF in BC. Through an RNAi-based screening, the CRL7^FBXW8 complex is identified as the E3 ligase complex responsible for NUMB hyper-degradation in BC. Genetic and pharmacological inhibition of CRL7^FBXW8 rescues the transformation-related phenotypes induced by NUMB LOF in BC cell lines and in patient-derived xenografts. These effects are directly

SUBMITTER: Sabbioni S 

PROVIDER: S-EPMC12224932 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature