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HER signaling:
targeting a critical receptor family

Human epidermal growth factor receptor (HER) pathways play a critical role in cancer biology and are an area of intense research at Genentech, a member of the Roche Group. Dysregulation of HER-mediated signaling pathways results in the growth and spread of cancer cells.1 The HER family consists of 4 structurally related receptors: HER1 (EGFR), HER2, HER3, and HER4.1,2 Normally, these receptors become primed for activation by the presence of ligands, such as growth factors.

Human Epidermal Growth Receptor (HER)
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HER family receptors are activated by ligand-induced dimerization, or receptor pairing.3 Dimerization is a critical step in HER family-mediated signaling, and HER receptors are able to homodimerize or heterodimerize with other HER family members, allowing for multiple receptor combinations.1,4

The formation of dimers leads to intracellular phosphorylation that provides docking sites for a variety of molecules. These molecules then relay signals to different downstream cascades, including the MAPK proliferation pathway and the PI3K/AKT prosurvival pathway-2 pathways frequently overactivated in cancer.1,4-7

Inappropriate signaling may occur as a result of receptor overexpression or dysregulation of receptor activation, which may lead to8-10

  • Increased/uncontrolled cell proliferation
  • Resistance to apoptosis (programmed cell death)
  • Enhanced cancer cell motility
  • Angiogenesis
References:
1.
Ménard S, Tagliabue E, Campiglio M, Pupa SM. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol. 2000;281:150-162.
2.
Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.
3.
Sorkin A, Goh LK. Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res. 2008;314:3093-3106.
4.
Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707-712.
5.
Holbro T, Civenni G, Hynes NE. The ErbB receptors and their role in cancer progression. Exp Cell Res. 2003;284:99-110.
6.
Lewis GD, Lofgren JA, McMurtrey AE, et al. Growth regulation of human breast and ovarian tumor cells by heregulin: evidence for the requirement of ErbB2 as a critical component in mediating heregulin responsiveness. Cancer Res. 1996;56:1457-1465.
7.
Campiglio M, Ali S, Knyazev PG, Ullrich A. Characteristics of EGFR family-mediated HRG signals in human ovarian cancer. J Cell Biochem. 1999;73:522-532.
8.
Prenzel N, Fischer OM, Streit S, et al. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer. 2001;8:11-31.
9.
Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta. 1994;1198:165-184.
10.
Linggi B, Carpenter G. ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol. 2006;16:649-656.