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Letter

Nature 451, 76-80 (3 January 2008) | doi:10.1038/nature06412; Received 1 March 2007; Accepted 23 October 2007

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NUMB controls p53 tumour suppressor activity

Ivan N. Colaluca1,2, Daniela Tosoni1,2, Paolo Nuciforo1, Francesca Senic-Matuglia1, Viviana Galimberti2, Giuseppe Viale2,3, Salvatore Pece1,2,3 & Pier Paolo Di Fiore1,2,3

  1. IFOM, the FIRC Institute for Molecular Oncology Foundation, Via Adamello 16, 20139, Milan, Italy
  2. European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy
  3. Dipartimento di Medicina, Chirurgia ed Odontoiatria, Università degli Studi di Milano, 20122 Milan, Italy

Correspondence to: Salvatore Pece1,2,3Pier Paolo Di Fiore1,2,3 Correspondence and requests for materials should be addressed to S.P. (Email: salvatore.pece@ifom-ieo-campus.it) or P.P.D.F (Email: pierpaolo.difiore@ifom-ieo-campus.it).

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NUMB is a cell fate determinant, which, by asymmetrically partitioning at mitosis, controls cell fate choices by antagonising the activity of the plasma membrane receptor of the NOTCH family1. NUMB is also an endocytic protein2, and the NOTCH–NUMB counteraction has been linked to this function3, 4. There might be, however, additional functions of NUMB, as witnessed by its proposed role as a tumour suppressor in breast cancer5. Here we describe a previously unknown function for human NUMB as a regulator of tumour protein p53 (also known as TP53). NUMB enters in a tricomplex with p53 and the E3 ubiquitin ligase HDM2 (also known as MDM2), thereby preventing ubiquitination and degradation of p53. This results in increased p53 protein levels and activity, and in regulation of p53-dependent phenotypes. In breast cancers there is frequent loss of NUMB expression5. We show that, in primary breast tumour cells, this event causes decreased p53 levels and increased chemoresistance. In breast cancers, loss of NUMB expression causes increased activity of the receptor NOTCH5. Thus, in these cancers, a single event—loss of NUMB expression—determines activation of an oncogene (NOTCH) and attenuation of the p53 tumour suppressor pathway. Biologically, this results in an aggressive tumour phenotype, as witnessed by findings that NUMB-defective breast tumours display poor prognosis. Our results uncover a previously unknown tumour suppressor circuitry.