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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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Numb expression in human mammary tumors. (A) The typical immunoreactivity for Numb in normal breast (normal) showed intense staining in the vast majority of ductal (luminal) and lobular epithelial cells, with a prominent membranous staining pattern. Examples are shown of typical class-1(type-0), class-2, and class-3 tumors. Arrowheads point to normal glands within the context of the tumors. (B) Correlation between Numb status and clinical-pathological features. Details and explanations are in Table S1, available at http://www.jcb.org/cgi/content/full/jcb.200406140/DC1. Ki67, proliferative index; LN, lymph nodes. P value was obtained using the Mantel-Haenszel Chi square statistics. (C) In situ hybridization with an antisense probe for Numb mRNA was performed on paraffin sections. Control hybridizations with a corresponding sense probe gave no signal (not depicted). Examples of matching bright fields (top) and dark fields (bottom) of class-1 (left) and class-3 (right) tumors are shown. Numb transcripts appear as bright spots in the dark fields (bottom).
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fig1: Numb expression in human mammary tumors. (A) The typical immunoreactivity for Numb in normal breast (normal) showed intense staining in the vast majority of ductal (luminal) and lobular epithelial cells, with a prominent membranous staining pattern. Examples are shown of typical class-1(type-0), class-2, and class-3 tumors. Arrowheads point to normal glands within the context of the tumors. (B) Correlation between Numb status and clinical-pathological features. Details and explanations are in Table S1, available at http://www.jcb.org/cgi/content/full/jcb.200406140/DC1. Ki67, proliferative index; LN, lymph nodes. P value was obtained using the Mantel-Haenszel Chi square statistics. (C) In situ hybridization with an antisense probe for Numb mRNA was performed on paraffin sections. Control hybridizations with a corresponding sense probe gave no signal (not depicted). Examples of matching bright fields (top) and dark fields (bottom) of class-1 (left) and class-3 (right) tumors are shown. Numb transcripts appear as bright spots in the dark fields (bottom).

Mentions: A preliminary survey of the expression of Numb in normal and tumor tissues of different origins (unpublished data) revealed frequent alterations in breast tumors. Thus, we characterized 321 consecutive breast cancers by immunohistochemistry (Table S1, available at http://www.jcb.org/cgi/content/full/jcb.200406140/DC1). The normal breast parenchyma invariably showed intense and homogeneous Numb staining (Fig. 1 A). Conversely, tumors displayed marked heterogeneity and in many cases complete absence of Numb immunoreactivity, which allowed their classification into three classes (Fig. 1 A). Class-1 (38.3% of the cases) tumors showed Numb staining in <10% of the neoplastic cells. Within this category, in fact, more than 50% of class-1 tumors displayed no detectable Numb immunoreactivity (type-0 tumors), whereas class-2 and -3 tumors (16.8% and 44.9% of investigated cases, respectively) showed Numb immunoreactivity in 10–50% and >50% of the tumor cells, respectively. Thus, more than one half of all breast tumors (classes 1 and 2 combined) had reduced levels of Numb. Remarkably, a strong inverse correlation was found between Numb expression levels and tumor grade (P = 0.001) and Ki67 labeling index (P = 0.001), which are known indicators of aggressive disease (Fig. 1 B and Table S1).


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)

Numb expression in human mammary tumors. (A) The typical immunoreactivity for Numb in normal breast (normal) showed intense staining in the vast majority of ductal (luminal) and lobular epithelial cells, with a prominent membranous staining pattern. Examples are shown of typical class-1(type-0), class-2, and class-3 tumors. Arrowheads point to normal glands within the context of the tumors. (B) Correlation between Numb status and clinical-pathological features. Details and explanations are in Table S1, available at http://www.jcb.org/cgi/content/full/jcb.200406140/DC1. Ki67, proliferative index; LN, lymph nodes. P value was obtained using the Mantel-Haenszel Chi square statistics. (C) In situ hybridization with an antisense probe for Numb mRNA was performed on paraffin sections. Control hybridizations with a corresponding sense probe gave no signal (not depicted). Examples of matching bright fields (top) and dark fields (bottom) of class-1 (left) and class-3 (right) tumors are shown. Numb transcripts appear as bright spots in the dark fields (bottom).
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Related In: Results  -  Collection

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fig1: Numb expression in human mammary tumors. (A) The typical immunoreactivity for Numb in normal breast (normal) showed intense staining in the vast majority of ductal (luminal) and lobular epithelial cells, with a prominent membranous staining pattern. Examples are shown of typical class-1(type-0), class-2, and class-3 tumors. Arrowheads point to normal glands within the context of the tumors. (B) Correlation between Numb status and clinical-pathological features. Details and explanations are in Table S1, available at http://www.jcb.org/cgi/content/full/jcb.200406140/DC1. Ki67, proliferative index; LN, lymph nodes. P value was obtained using the Mantel-Haenszel Chi square statistics. (C) In situ hybridization with an antisense probe for Numb mRNA was performed on paraffin sections. Control hybridizations with a corresponding sense probe gave no signal (not depicted). Examples of matching bright fields (top) and dark fields (bottom) of class-1 (left) and class-3 (right) tumors are shown. Numb transcripts appear as bright spots in the dark fields (bottom).
Mentions: A preliminary survey of the expression of Numb in normal and tumor tissues of different origins (unpublished data) revealed frequent alterations in breast tumors. Thus, we characterized 321 consecutive breast cancers by immunohistochemistry (Table S1, available at http://www.jcb.org/cgi/content/full/jcb.200406140/DC1). The normal breast parenchyma invariably showed intense and homogeneous Numb staining (Fig. 1 A). Conversely, tumors displayed marked heterogeneity and in many cases complete absence of Numb immunoreactivity, which allowed their classification into three classes (Fig. 1 A). Class-1 (38.3% of the cases) tumors showed Numb staining in <10% of the neoplastic cells. Within this category, in fact, more than 50% of class-1 tumors displayed no detectable Numb immunoreactivity (type-0 tumors), whereas class-2 and -3 tumors (16.8% and 44.9% of investigated cases, respectively) showed Numb immunoreactivity in 10–50% and >50% of the tumor cells, respectively. Thus, more than one half of all breast tumors (classes 1 and 2 combined) had reduced levels of Numb. Remarkably, a strong inverse correlation was found between Numb expression levels and tumor grade (P = 0.001) and Ki67 labeling index (P = 0.001), which are known indicators of aggressive disease (Fig. 1 B and Table S1).

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