The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment Through Regulation of NUMB Levels

Sabbioni, S.; Filippone, M. G.; Amadori, L.; Confalonieri, S.; Bonfanti, R.; Capoano, S.; Colaluca, I. N.; Freddi, S.; Bertalot, G.; Faga, G.; Zagarri, E.; Varasi, M.; Gunby, R. H.; Mercurio, C.; Pece, S.; Di Fiore, P. P.; Tosoni, D.

doi:10.1101/2025.02.27.640530

bioRxiv · 10.1101/2025.02.27.640530

The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment Through Regulation of NUMB Levels

Sabbioni, S.·Filippone, M. G.·Amadori, L.·Confalonieri, S.·Bonfanti, R.·Capoano, S.·Colaluca, I. N.·Freddi, S.·Bertalot, G.·Faga, G.·Zagarri, E.·Varasi, M.·Gunby, R. H.·Mercurio, C.·Pece, S.·Di Fiore, P. P.·Tosoni, D.

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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, 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 CRL7FBXW8 complex as the E3 ligase complex responsible for NUMB hyper-degradation in BC. Genetic and pharmacological inhibition of CRL7FBXW8 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 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.

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Sabbioni, S., Filippone, M. G., Amadori, L., Confalonieri, S., Bonfanti, R., Capoano, S., Colaluca, I. N., Freddi, S., Bertalot, G., Faga, G., Zagarri, E., Varasi, M., Gunby, R. H., Mercurio, C., Pece, S., Di Fiore, P. P., Tosoni, D.. 2025-03-03. The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment Through Regulation of NUMB Levels. https://doi.org/10.1101/2025.02.27.640530

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