The CRL7 <sup>FBXW8</sup> Complex 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, 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<sup>FBXW8</sup> complex is identified as the E3 ligase complex responsible for NUMB hyper-degradation in BC. Genetic and pharmacological inhibition of CRL7<sup>FBXW8</sup> rescues the transformation-related phenotypes induced by NUMB LOF in BC cell lines and in patient-derived xenografts. These effects are directly dependent on the restoration of NUMB protein levels. Thus, enhanced CRL7<sup>FBXW8</sup> 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.
Authors
- Stefano Confalonieri (ORCID: https://orcid.org/0000-0001-6886-9851)
- Maria Grazia Filippone
- Daniela Tosoni (ORCID: https://orcid.org/0000-0003-4443-1059)
- Ciro Mercurio (ORCID: https://orcid.org/0000-0001-6240-4607)
- Giovanni Bertalot (ORCID: https://orcid.org/0000-0002-4862-7705)
- Pier Paolo Di Fiore (ORCID: https://orcid.org/0000-0002-2252-0950)
- Letizia Amadori (ORCID: https://orcid.org/0000-0003-1125-4631)
- Stefano Freddi (ORCID: https://orcid.org/0000-0003-4263-3060)
- Elisa Zagarrí
- Roberta Bonfanti
- Rosalind H. Gunby (ORCID: https://orcid.org/0000-0002-4359-3884)
- Salvatore Pece (ORCID: https://orcid.org/0000-0003-1764-3929)
- Ivan Nicola Colaluca (ORCID: https://orcid.org/0000-0002-3371-112X)
- Giovanni Fagà (ORCID: https://orcid.org/0000-0002-7674-2583)
- Mario Varasi (ORCID: https://orcid.org/0000-0003-0367-8290)
- Silvia Sabbioni (ORCID: https://orcid.org/0000-0002-1565-8214)
- Stefano Capoano
Institutions
- University of Milan (IT)
- European Institute of Oncology (IT)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-05-24
- DOI
- https://doi.org/10.1002/advs.202405812
- Citations
- 3
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Ministero della Salute
- Ministero dell’Istruzione, dell’Università e della Ricerca