The CRL7FBXW8 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 caus...
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Wiley
2025-07-01
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| Online Access: | https://doi.org/10.1002/advs.202405812 |
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| author | Simone Sabbioni Maria Grazia Filippone Letizia Amadori Stefano Confalonieri Roberta Bonfanti Stefano Capoano Ivan Nicola Colaluca Stefano Freddi Giovanni Bertalot Giovanni Fagà Elisa Zagarrí Mario Varasi Rosalind Helen Gunby Ciro Mercurio Salvatore Pece Pier Paolo Di Fiore Daniela Tosoni |
| author_facet | Simone Sabbioni Maria Grazia Filippone Letizia Amadori Stefano Confalonieri Roberta Bonfanti Stefano Capoano Ivan Nicola Colaluca Stefano Freddi Giovanni Bertalot Giovanni Fagà Elisa Zagarrí Mario Varasi Rosalind Helen Gunby Ciro Mercurio Salvatore Pece Pier Paolo Di Fiore Daniela Tosoni |
| author_sort | Simone Sabbioni |
| collection | DOAJ |
| description | 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 CRL7FBXW8 complex is identified as the E3 ligase complex responsible for NUMB hyper‐degradation in BC. Genetic and pharmacological inhibition of CRL7FBXW8 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 CRL7FBXW8 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. |
| format | Article |
| id | doaj-art-aaed62535a5d40a7b9dfa37079c44361 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-aaed62535a5d40a7b9dfa37079c443612025-08-20T03:28:58ZengWileyAdvanced Science2198-38442025-07-011225n/an/a10.1002/advs.202405812The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment through Regulation of NUMB LevelsSimone Sabbioni0Maria Grazia Filippone1Letizia Amadori2Stefano Confalonieri3Roberta Bonfanti4Stefano Capoano5Ivan Nicola Colaluca6Stefano Freddi7Giovanni Bertalot8Giovanni Fagà9Elisa Zagarrí10Mario Varasi11Rosalind Helen Gunby12Ciro Mercurio13Salvatore Pece14Pier Paolo Di Fiore15Daniela Tosoni16IEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyIEO European Institute of Oncology IRCCS Milan 20139 ItalyAbstract 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 CRL7FBXW8 complex is identified as the E3 ligase complex responsible for NUMB hyper‐degradation in BC. Genetic and pharmacological inhibition of CRL7FBXW8 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 CRL7FBXW8 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.https://doi.org/10.1002/advs.202405812breast cancercancer stem cellsCRL7FBXW8 complexNUMBproteasomal degradation |
| spellingShingle | Simone Sabbioni Maria Grazia Filippone Letizia Amadori Stefano Confalonieri Roberta Bonfanti Stefano Capoano Ivan Nicola Colaluca Stefano Freddi Giovanni Bertalot Giovanni Fagà Elisa Zagarrí Mario Varasi Rosalind Helen Gunby Ciro Mercurio Salvatore Pece Pier Paolo Di Fiore Daniela Tosoni The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment through Regulation of NUMB Levels Advanced Science breast cancer cancer stem cells CRL7FBXW8 complex NUMB proteasomal degradation |
| title | The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment through Regulation of NUMB Levels |
| title_full | The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment through Regulation of NUMB Levels |
| title_fullStr | The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment through Regulation of NUMB Levels |
| title_full_unstemmed | The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment through Regulation of NUMB Levels |
| title_short | The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment through Regulation of NUMB Levels |
| title_sort | crl7fbxw8 complex controls the mammary stem cell compartment through regulation of numb levels |
| topic | breast cancer cancer stem cells CRL7FBXW8 complex NUMB proteasomal degradation |
| url | https://doi.org/10.1002/advs.202405812 |
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