Epidermal growth factor receptors in breast cancer: from experiment to clinical practice

Abstract

The role of auto-paracrine regulation of cell proliferation in breast cancer is analyzed. Experimental data indicate that the epidermal growth factor receptor is the key transmitter of mitogenic signals from the polypeptide growth factors and participates in the formation of sensitivity and/or resistance of breast cancer cells to steroid hormones. Data of representative clinical studies indicate that the expression of the epidermal growth factor receptor is prognostically unfavorable in breast cancer. Screening of patients with breast tumors for this receptor will detect the high-risk group at early stages of the disease. A scheme of the screening is proposed.Key Words: epidermal growth factor receptors; breast cancer; proliferation regulation; steroid hormone sensitivity; prognosis Epidermal growth factor receptor (EGFR) is a large transmembrane glycoprotein with a molecular weight of 170 kD. It is a product of an erb-c-erbB1 oncogene and belongs to so-called tyrosine kinases that are important regulators of cell proliferation and malignant transformation [17,32,46]. Transmembrane localization and need in relevant polypeptide ligand for realization of the kinase activity differs the receptor tyrosine kinases from the nonreceptor ones, which are also products of some important oncogenes, for example, v-src, v-abl, and bcr-abl.In addition to the epidermal growth factor (EGF), m-transforming growth factor (c~-TGR), Vaccinia virus growth factor, and the peptides amphiregulin, cripto and [3-cellulin binding heparin EGF-like factor act as specific EGFR ligands [12,23,53,75]. All these ligands are polypeptides consisting of about 40 amino acids with a molecular weight of about 6 kD. They are 24-40% homologous by primary structure and similar by spatial configuration due to con- Like molecules of all receptor tyrokinases, a EGRF molecule contains 3 major domains [17,75]: extracellular N-terminal glycosylated ligand-binding site constituting about 50% of the molecule (621 of 1173 amino acid residues) and ensuring specificity of the signal perception, transmembrane o~-spiral site consisting of only 23 hydrophobic amino acids, and intracellular tyrosine kinase domain (542 amino acids) similar in all receptor tyrokinases.Schematically, all main events in which EGFR is involved as a result of its reaction with the ligand are as follows [17,54,61,62,69,75]: immediately after the ligand binding, the receptor is dimerized, which leads to tyrosine kinase activation and autophosphorylation of tyrosine residues of the C-terminal domain and alteration of its conformation, thus promoting binding and phosphorylation of exogenous substrates and subsequent competitive inhibition of the receptor autophosphorylation. After autophos-0007-4888/98/0011-1073520.00 9Kluwer Academic/Plenum Publishers

Soluble fragment of Her2/neu receptor in the serum of patients with breast cancer with different levels of this protein expression in the tumor

“…EGFR family receptors form homo-and heterodimers upon activation. In many cases, structures containing type 2 receptor HER2/ neu, which has no specific ligands, are most active [1,4,10]. Hence, HER2/neu is a unique dispatcher receptor which does not interact with any of the known growth factors activating related receptors, but is a key component in transmission of mitogenic signals of all EGF-like peptides.…”