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

Pece S, Serresi M, Santolini E, Capra M, Hulleman E, Galimberti V, Zurrida S, Maisonneuve P, Viale G, Di Fiore PP - J. Cell Biol. (2004)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy.

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 approximately 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.

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Re-expression of Numb selectively suppresses growth in Numb-negative tumors. (A) Primary tumor cells from class-1(type-0) (left) and class-3 (right) patients were transduced with retroviruses encoding GFP or Numb-GFP. After 3 wk, plates were fixed and stained (bottom). The histograms show the average number of colonies (colony-forming units ± SD) from three plates. Similar results were obtained with primary cultures from three independent class-1(type-0) and three independent class-3 patients (not depicted). (B) The expression of GFP and Numb-GFP, as detected by epifluorescence (top) or immunoblot (bottom), upon transient retroviral delivery is shown to demonstrate equal efficiency of infection/expression.
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fig3: Re-expression of Numb selectively suppresses growth in Numb-negative tumors. (A) Primary tumor cells from class-1(type-0) (left) and class-3 (right) patients were transduced with retroviruses encoding GFP or Numb-GFP. After 3 wk, plates were fixed and stained (bottom). The histograms show the average number of colonies (colony-forming units ± SD) from three plates. Similar results were obtained with primary cultures from three independent class-1(type-0) and three independent class-3 patients (not depicted). (B) The expression of GFP and Numb-GFP, as detected by epifluorescence (top) or immunoblot (bottom), upon transient retroviral delivery is shown to demonstrate equal efficiency of infection/expression.

Mentions: The possibility that enhanced degradation of Numb is causally involved in the progression of breast cells toward malignancy prompted us to test the consequences of restoration of Numb levels in primary tumor cells. Retrovirally mediated transient overexpression of a fusion Numb-GFP protein in primary cells from class-1 tumors resulted in a clear reduction in colony-forming ability (Fig. 3 A). Conversely, class-3 tumor cells were unaffected, despite similar levels of Numb-GFP expression upon transient infection (Fig. 3 B).


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

Pece S, Serresi M, Santolini E, Capra M, Hulleman E, Galimberti V, Zurrida S, Maisonneuve P, Viale G, Di Fiore PP - J. Cell Biol. (2004)

Re-expression of Numb selectively suppresses growth in Numb-negative tumors. (A) Primary tumor cells from class-1(type-0) (left) and class-3 (right) patients were transduced with retroviruses encoding GFP or Numb-GFP. After 3 wk, plates were fixed and stained (bottom). The histograms show the average number of colonies (colony-forming units ± SD) from three plates. Similar results were obtained with primary cultures from three independent class-1(type-0) and three independent class-3 patients (not depicted). (B) The expression of GFP and Numb-GFP, as detected by epifluorescence (top) or immunoblot (bottom), upon transient retroviral delivery is shown to demonstrate equal efficiency of infection/expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172557&req=5

fig3: Re-expression of Numb selectively suppresses growth in Numb-negative tumors. (A) Primary tumor cells from class-1(type-0) (left) and class-3 (right) patients were transduced with retroviruses encoding GFP or Numb-GFP. After 3 wk, plates were fixed and stained (bottom). The histograms show the average number of colonies (colony-forming units ± SD) from three plates. Similar results were obtained with primary cultures from three independent class-1(type-0) and three independent class-3 patients (not depicted). (B) The expression of GFP and Numb-GFP, as detected by epifluorescence (top) or immunoblot (bottom), upon transient retroviral delivery is shown to demonstrate equal efficiency of infection/expression.
Mentions: The possibility that enhanced degradation of Numb is causally involved in the progression of breast cells toward malignancy prompted us to test the consequences of restoration of Numb levels in primary tumor cells. Retrovirally mediated transient overexpression of a fusion Numb-GFP protein in primary cells from class-1 tumors resulted in a clear reduction in colony-forming ability (Fig. 3 A). Conversely, class-3 tumor cells were unaffected, despite similar levels of Numb-GFP expression upon transient infection (Fig. 3 B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy.

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 approximately 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.

Show MeSH
Related in: MedlinePlus