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Titre du document / Document title

Molecular mechanisms underlying ErbB2/HER2 action in breast cancer

Auteur(s) / Author(s)

HARARI Daniel (1) ; YARDEN Yosef (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Department of Biological Regulation, the Weizmann Institute of Science, Rehovot 76100, ISRAEL

Résumé / Abstract

Overexpression of ErbB2, a receptor-like tyrosine kinase, is shared by several types of human carcinomas. In breast tumors the extent of overexpression has a prognostic value, thus identifying the oncoprotein as a target for therapeutic strategies. Already, antibodies to ErbB2 are used in combination with chemotherapy in the treatment of metastasizing breast cancer. The mechanisms underlying the oncogenic action of ErbB2 involve a complex network in which ErbB2 acts as a ligand-less signaling subunit of three other receptors that directly bind a large repertoire of stroma-derived growth factors. The major partners of ErbB2 in carcinomas are ErbB1 (also called EGFR) and ErbB3, a kinase-defective receptor whose potent mitogenic action is activated in the context of heterodimeric complexes. Why ErbB2-containing heterodimers are relatively oncopotent is a function of a number of processes. Apparently, these heterodimers evade normal inactivation processes, by decreasing the rate of ligand dissociation, internalizing relatively slowly and avoiding the degradative pathway by returning to the cell surface. On the other hand, the heterodimers strongly recruit survival and mitogenic pathways such as the mitogen-activated protein kinases and the phosphatidylinositol 3-kinase. Hyper-activated signaling through the ErbB-signaling network results in dysregulation of the cell cycle homeostatic machinery, with upregulation of active cyclin-D/CDK complexes. Recent data indicate that cell cycle regulators are also linked to chemoresistance in ErbB2-dependent breast carcinoma. Together with D-type cyclins, it seems that the CDK inhibitor p21Waf1 plays an important role in evasion from apoptosis. These recent findings herald a preliminary understanding of the output layer which connects elevated ErbB-signaling to oncogenesis and chemoresistance.

Revue / Journal Title

Oncogene    ISSN  0950-9232 

Source / Source

2000, vol. 19, no 53 (93 p.)  (3 p.1/4), pp. 6102-6114

Langue / Language

Anglais

Editeur / Publisher

Nature Publishing Group, Basingstoke, ROYAUME-UNI  (1987) (Revue)

Mots-clés anglais / English Keywords

Review

;

Human

;

Malignant tumor

;

Mammary gland

;

Gene expression

;

Biological receptor

;

Signal transduction

;

Growth factor

;

Cell cycle

;

C-Onc gene

;

Cyclin D1

;

Membrane receptor

;

Protein-tyrosine kinase

;

Transferases

;

Enzyme

;

Mots-clés français / French Keywords

Article synthèse

;

Homme

;

Tumeur maligne

;

Glande mammaire

;

Expression génique

;

Récepteur biologique

;

Transduction signal

;

Facteur croissance

;

Cycle cellulaire

;

Gène onc cellulaire

;

Cycline D1

;

Protéine erbB

;

Protéine Cip1

;

Récepteur membranaire

;

Protein-tyrosine kinase

;

Transferases

;

Enzyme

;

Mots-clés espagnols / Spanish Keywords

Artículo síntesis

;

Hombre

;

Tumor maligno

;

Glándula mamaria

;

Expresión genética

;

Receptor biológico

;

Transducción señal

;

Factor crecimiento

;

Ciclo celular

;

Gen onc celular

;

Cyclina D1

;

Receptor membrana

;

Protein-tyrosine kinase

;

Transferases

;

Enzima

;

Localisation / Location

INIST-CNRS, Cote INIST : 21693, 35400009400046.0020

Nº notice refdoc (ud4) : 899737



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