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Explore HER Pathways and Signaling

HER signaling pathways and cancer

Human epidermal growth factor receptor (HER) signaling has been linked to cancer. When HER signaling pathways are activated, growth and spread of cancer cells may result.1 Because of their involvement in tumor biology, HER family receptors represent an ongoing area of cancer research.2

Activated HER signaling pathways

HER pathways

The HER family of receptors

Cellular receptors are responsible for translating signals from outside the cell into signals within the cell. These signals have numerous effects (such as growth, proliferation, and survival), and receptor activation is tightly regulated in normal cells.2

The HER family consists of 4 structurally related cellular receptors, which interact in many ways.1,3 They include HER1 (EGFR), HER2, HER3, and HER4. HER1/EGFR, HER3, and HER4 are each associated with one or more specific ligands, whereas there are no known ligands that bind HER2.1,4

Structure of HER family receptors

HER receptor structure

HER receptor activation

Receptor activation is a multistep process. After ligand binding, receptors dimerize, or form pairs.2 Upon dimerization, the intracellular tyrosine kinase domains of the receptors are phosphorylated, activating the receptors and initiating downstream signaling cascades, such as the MAPK proliferation pathway and/or the PI3K/AKT prosurvival pathway.1

With 4 members of the HER family of receptors, each of which is able to homodimerize or to heterodimerize with other members of the HER family, multiple receptor combinations are possible.2 HER2 is the preferred dimerization partner for all members of the HER receptor family since it exists in an open conformation and is continually available for dimerization.1,2,5

HER receptor activation

This diagram illustrates the effects of HER receptor dimerization and subsequent activation. After ligand binding, receptors dimerize, or form pairs. Upon dimerization, the intracellular tyrosine kinase domains of the receptors are phosphorylated, activating the receptors and initiating downstream signaling.1 Role of HER2 gene expression in breast carcinoma. Ménard S, Tagliabue E, Campiglio M, Pupa SM. Copyright © 2000 J Cell Phys. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Inappropriate activation of HER family receptors

In normal cells, the process of HER activation is closely regulated, keeping cell growth under control. In cancer, HER receptors may be inappropriately activated, leading to uncontrolled growth and spread of tumor cells.6

Overexpression of HER receptors can lead to increased signaling, and genetic mutations can lead to the production of HER receptors that can be activated even without ligand binding.7 When tumors express both HER family receptors and their associated ligands, an autocrine loop, in which the tumor stimulates its own growth, can result.6

HER dysregulation1

HER dysregulation

HER2 amplification and overexpression

Dysregulation of HER2 signaling in cancer involves an excess of signals that stimulate cancer cells to grow and spread.6-9 It is this excess of signals, rather than a mutation in the receptor itself, that results in the deleterious effects of HER2 in cancer. In fact, HER2 gene amplification and receptor overexpression occur in about 25% of breast cancers.10

    • Ménard S, Tagliabue E, Campiglio M, Pupa SM. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol. 2000;281:150-162. PMID: 10623878

      Ménard S, Tagliabue E, Campiglio M, Pupa SM. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol. 2000;281:150-162. PMID: 10623878

    • 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.

      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.

    • Burgess AW, Cho HS, Elgenbrot C, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell. 2003;12:541-542. PMID: 14527402

      Burgess AW, Cho HS, Elgenbrot C, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell. 2003;12:541-542. PMID: 14527402

    • Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159-3167. PMID: 10880430

      Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159-3167. PMID: 10880430

    • Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997;16:1647-1655. PMID: 9130710

      Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997;16:1647-1655. PMID: 9130710

    • 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. PMID: 11350724

      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. PMID: 11350724

    • Ejskjaer K, Sørensen BS, Poulsen SS, et al. Expression of the epidermal growth factor system in endometrioid endometrial cancer. Gynecol Oncol. 2007;104:158-167. PMID: 16962163

      Ejskjaer K, Sørensen BS, Poulsen SS, et al. Expression of the epidermal growth factor system in endometrioid endometrial cancer. Gynecol Oncol. 2007;104:158-167. PMID: 16962163

    • Edwards J, Traynor P, Munro AF, Pirret CF, Dunne B, Bartlett JM. The role of HER1-HER4 and EGFRvIII in hormone-refractory prostate cancer. Clin Cancer Res. 2006;12:123-130. PMID: 16397033

      Edwards J, Traynor P, Munro AF, Pirret CF, Dunne B, Bartlett JM. The role of HER1-HER4 and EGFRvIII in hormone-refractory prostate cancer. Clin Cancer Res. 2006;12:123-130. PMID: 16397033

    • Baker CH, Pino MS, Fidler IJ. Phosphorylated epidermal growth factor receptor on tumor-associated endothelial cells in human renal cell carcinoma is a primary target for therapy by tyrosine kinase inhibitors. Neoplasia. 2006;8:470-476. PMID: 16820093

      Baker CH, Pino MS, Fidler IJ. Phosphorylated epidermal growth factor receptor on tumor-associated endothelial cells in human renal cell carcinoma is a primary target for therapy by tyrosine kinase inhibitors. Neoplasia. 2006;8:470-476. PMID: 16820093

    • 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. PMID: 2470152

      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. PMID: 2470152

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