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Human Epidermal Growth Factor Receptor (HER) Signaling

Growth factors — such as human epidermal growth factor — that bind to cell-surface receptors are important regulators of normal cell proliferation and survival.¹ Dysregulation of signal transduction pathways, including overexpression of growth factor receptors, is one of the fundamental elements contributing to the growth and progression of many solid tumors.¹

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HER cellular signaling is initiated when two receptor molecules join together in a process called dimerization, which occurs in response to the presence of a growth factor molecule (ligand).⁵⁰

There are four known HER proteins: HER1, 2, 3, and 4. HER2 is able to dimerize with itself (homodimerization), and while there is no known ligand for HER2, this receptor plays a pivotal role in HER-mediated signaling as the preferred partner for dimerization with HER1, 3, and 4 (heterodimerization), the most potent combination of which appears to be the HER2/HER3 dimer.⁵⁰

Dimerization of different members of this family, including HER1, HER2, HER3, and HER4, may lead to activation of different kinase-mediated intracellular signaling cascades, including the PI3K and MAPK pathways, although to date, no HER3-associated kinase activity has been identified.^48,50,51

Inappropriate signaling can occur as a result of overexpression of receptor proteins or when receptors are expressed at normal levels but are inappropriately activated. HER overexpression and/or dysregulation may lead to increased/uncontrolled proliferation, decreased apoptosis (programmed cell death), enhanced tumor cell motility, and angiogenesis.^48,49,52

Genentech has been a pioneer in researching the complex HER signaling network and understanding its role in the progression of cancer.⁴¹ In the 1980s, Genentech researcher Axel Ullrich was the first to clone the human gene for epidermal growth factor receptor (EGFR).⁴² Further experiments by Ullrich led to the discovery of a related receptor, which was cloned in collaboration with current Chief Executive Officer Art Levinson and other scientists at Genentech.⁴¹ The structure of this newly found gene, HER2, was revealed to be closely related to a known avian oncogene, raising the possibility that HER2 could play a role in human cancer.^43,44

Current research shows that HER2 is overexpressed as a result of gene amplification in about 25% of patients with breast cancer.^45-47 In addition, HER family dimerization initiates signaling cascades that mediate cancer cell growth.^48,49 By understanding these signaling pathways, we can gain greater insight into the molecular processes leading to cancer. Genentech BioOncology continues to study the HER signaling pathway with the goal of identifying potential therapeutic targets for the prevention of cancer cell proliferation and metastasis.

Journal Articles

1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.

41. Coussens L, Yang-Feng TL, Liao YC, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985;230:1132-1139.

42. Ullrich A, Coussens L, Hayflick JS, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature. 1984;309:418-425.

43. Downward J, Yarden Y, Mayes E, et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature. 1984;307:521-527.

44. Mendelsohn J. Blockade of receptors for growth factors: an anticancer therapy — the Fourth Annual Joseph H Burchenal American Association for Cancer Research Clinical Research Award Lecture. Clin Cancer Res. 2000;6:747-753.

45. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177-182.

46. Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer. 2004;5:63-69.

47. Lal P, Salazar PA, Hudis CA, Ladanyi M, Chen B. HER-2 testing in breast cancer using immunohistochemical analysis and fluorescence in situ hybridization: a single-institution experience of 2,279 cases and comparison of dual-color and single-color scoring. Am J Clin Pathol. 2004;121:631-636.

48. 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.

49. Linggi B, Carpenter G. ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol. 2006;16:649-656.

50. Sundaresan S, Penuel E, Sliwkowski MX. The biology of human epidermal growth factor receptor 2. Curr Oncol Rep. 1999;1:16-22.

51. Spivak-Kroizman T, Rotin D, Pinchasi D, et al. Heterodimerization of c-erbB2 with different epidermal growth factor receptor mutants elicits stimulatory or inhibitory responses. J Biol Chem. 1992;267:8056-8063.

52. Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta. 1994;1198:165-184.

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