The role of erbB-2 and its ligands in growth control of malignant breast epithelium.

R. Lupu, R. B. Dickson, Marc E Lippman

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

A wealth of recently derived information has strongly implicated the protooncogene erbB-2 (also termed HER-2 or neu) and its protein product as critically involved in human breast cancer as well as other important epithelial malignancies. Because of its substantial homology with the EGF receptor, erbB-2 has long been assumed to encode a growth factor receptor, although until recently definitive identification of ligand(s) has remained elusive. Both in a mutated form and when overexpressed in a non-mutated form, erbB-2 is capable of inducing malignant transformation of many target cells including immortalized breast epithelium. We have recently identified and purified a 30 kDa size growth factor secreted by some human breast cancer cells. The factor is related to transforming growth factor-alpha (TGF-alpha) in its ability to bind to the epidermal growth factor (EGF) receptor (though with about 10 fold lower apparent affinity), its ability to phosphorylate EGF receptor and its ability to induce cloning of normal rat kidney (NRK) fibroblasts. However, it is distinct from TGF-alpha as determined by peptide mapping and its ability to induce activation of erbB-2. TGF-alpha and EGF are incapable of directly inducing phosphorylation of erbB-2. However, in a variety of spontaneously occurring tumor cells as well as cell lines transfected with erbB-2 prepared in our laboratory, 30 kDa glycoprotein (gp30) is capable of inducing direct phosphorylation of erbB-2. The ability to induce phosphorylation of erbB-2 is not inhibited by an anti-EGF receptor blocking antibody. In cells that overexpress erbB-2, the gp30 low concentrations is stimulatory of both standard mitogenesis assays and in clonogenic assays. At higher concentrations, the ligand is growth inhibitory in both of these assays. Because of the ability of gp30 to compete for binding with antibodies directed against erbB-2 which inhibit growth, the gp30 ligand is capable of reversing antibody-induced inhibition of growth. In addition, the gp30 ligand can overcome inhibitory effects seen in cells which overexpress erbB-2 which are induced by extracellular domain fragments of the erbB-2 receptor, once again suggesting a specific pathway of action for the gp30 ligand mediated for interaction with erbB-2.(ABSTRACT TRUNCATED AT 400 WORDS)

Original languageEnglish
Pages (from-to)49-60
Number of pages12
JournalPrincess Takamatsu symposia
Volume22
StatePublished - Dec 1 1991
Externally publishedYes

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Breast
Epidermal Growth Factor Receptor
Epithelium
Transforming Growth Factor alpha
Ligands
Growth
Phosphorylation
ErbB-2 Receptor
Breast Neoplasms
Blocking Antibodies
Peptide Mapping
Growth Factor Receptors
Antibodies
Epidermal Growth Factor
Organism Cloning
Neoplasms
Intercellular Signaling Peptides and Proteins
Glycoproteins
Fibroblasts
Kidney

ASJC Scopus subject areas

  • Medicine(all)

Cite this

The role of erbB-2 and its ligands in growth control of malignant breast epithelium. / Lupu, R.; Dickson, R. B.; Lippman, Marc E.

In: Princess Takamatsu symposia, Vol. 22, 01.12.1991, p. 49-60.

Research output: Contribution to journalArticle

Lupu, R. ; Dickson, R. B. ; Lippman, Marc E. / The role of erbB-2 and its ligands in growth control of malignant breast epithelium. In: Princess Takamatsu symposia. 1991 ; Vol. 22. pp. 49-60.
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