Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis

Abstract

The biological antagonism between Notch and Numb controls the proliferative/differentiative balance in development and homeostasis. Although altered Notch signaling has been linked to human diseases, including cancer, evidence for a substantial involvement of Notch in human tumors has remained elusive. Here, we show that Numb-mediated control on Notch signaling is lost in ∼50% of human mammary carcinomas, due to specific Numb ubiquitination and proteasomal degradation. Mechanistically, Numb operates as an oncosuppressor, as its ectopic expression in Numb-negative, but not in Numb-positive, tumor cells inhibits proliferation. Increased Notch signaling is observed in Numb-negative tumors, but reverts to basal levels after enforced expression of Numb. Conversely, Numb silencing increases Notch signaling in normal breast cells and in Numb-positive breast tumors. Finally, growth suppression of Numb-negative, but not Numb-positive, breast tumors can be achieved by pharmacological inhibition of Notch. Thus, the Numb/Notch biological antagonism is relevant to the homeostasis of the normal mammary parenchyma and its subversion contributes to human mammary carcinogenesis.

Numb regulates vesicular docking for homotypic fusion of early endosomes via membrane recruitment of Mon1b

“…Numb carries out these functions via regulating endocytic trafficking of several key molecules, such as Notch, sanpodo, cadherins and integrins [4,7,9,14,17,18,23,24,26,51,52]. Although in all these contexts Numb functions as an endocytic adaptor protein, the exact role of Numb in endocytic trafficking remains an open question.…”

“…Mammals have two Numb homologs, Numb and Numblike, which play redundant but distinct roles in various cellular processes such as asymmetric cell division, cell differentiation, migration, stem cell activation, adherens junction maintenance, tissue regeneration, tumorigenesis and even Alzheimer's disease-related beta-amyloid precursor protein (APP) cleavage [4][5][6][7][8][9][10][11][12][13][14]. There are at least four major alternatively spliced isoforms of Numb, with different combinations of an 11-amino acid insert in the phosphotyrosine-binding (PTB) domain and a 48-amino acid insert in the proline-rich region, generating four proteins: Numb 65, Numb 66, Numb 71 and Numb 72.…”

NUMB is a break of WNT - Notch signaling cycle

“…NUMBmediated Notch signaling inhibition is lost in a large proportion of human breast cancer due to ubiquitination-dependent NUMB degradation, which results in Notch signaling activation and induction of carcinogenesis (46,47). NUMB is a tumor suppressor gene maintaining homeostasis of stem and progenitor cells through the inhibition of Notch signaling.…”

Somatic stem cells and the origin of cancer

“…A human homologue of the Drosophila gene LgL is HUGL1, which controls cell polarity and is commonly inactivated in cancer in humans and in mice [115][116][117] . Last, inactivation of Numb may in turn activate the Notch signalling pathway, commonly observed in human solid and hematopoietic tumors 118,119 . It may be hypothesized that APC mutations occurring in intestinal epithelial stem cells, HUGL1 or Numb alterations may lead to cancer by altering asymmetric cell division.…”