The CRL7FBXW8Complex Controls the Mammary Stem Cell Compartment Through Regulation of NUMB Levels

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, we establish that loss of NUMB protein, resulting from protein hyper-degradation, is the prevalent mechanism of NUMB LOF in BC. Through a RNAi-based screening, we identified the CRL7 FBXW8 complex as the E3 ligase complex responsible for NUMB hyper-degradation in BC. Genetic and pharmacological inhibition of CRL7 FBXW8 rescued the transformation-related phenotypes induced by NUMB LOF in BC cell lines and in patient-derived xenografts. These effects were directly dependent on the restoration of NUMB protein levels. Thus, enhanced CRL7 FBXW8 activity, through its interference with the tumor suppressor activity of NUMB, is a causal alteration in BC, suggesting it as a potential therapeutic target for precision medicine.