The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

Abstract

The year 2007 marks exactly two decades since Human Epidermal Growth Factor Receptor-2 (HER2) was functionally implicated in the pathogenesis of human breast cancer. This finding established the HER2 oncogene hypothesis for the development of some human cancers. The subsequent two decades have brought about an explosion of information about the biology of HER2 and the HER family. An abundance of experimental evidence now solidly supports the HER2 oncogene hypothesis and etiologically links amplification of the HER2 gene locus with human cancer pathogenesis. The molecular mechanisms underlying HER2 tumorigenesis appear to be complex and a unified mechanistic model of HER2-induced transformation has not emerged. Numerous hypotheses implicating diverse transforming pathways have been proposed and are individually supported by experimental models and HER2 may indeed induce cell transformation through multiple mechanisms. Here I review the evidence supporting the oncogenic function of HER2, the mechanisms that are felt to mediate its oncogenic functions, and the evidence that links the experimental evidence with human cancer pathogenesis.

Figure 1

Structure of the HER2 and Neu proteins. The domain structure is shown on the left consisting of two ligand binding regions (LD1 & LD2), two cysteine-rich regions (CR1 & CR2), a short transmembrane domain (TM), a catalytic tyrosine kinase domain (TK), and a carboxy terminal tail (CT). Numerous sites of tyrosine phosphorylation wiithin the TK and CT domains are indicated by circled P.The letters on the right point to specific areas that are altered or mutated in certain naturally occuring or experimentally induced cancers discussed in the text. A) site of somatic mutations found in tumors arising in MMTV-neu mice. B) site of the 48bp deletion in the naturally occuring human ΔHER2 isoform. C) site of the mutation in the neuT oncogene initially discovered in a rat carcinogen induced tumor model and subsequently used in numerous in vitro and transgenic experimental models. D) site of mutations found in rare cases of human lung cancers.

Figure 2

FISH analysis of HER2 amplification. A human breast cancer specimen hybridized with a HER2 gene probe (in green) and a chromosome 17 centromeric probe (in red) showing significantly increased HER2 gene copy number compared with the chromosome 17 control. (Hicks and Tubbs 2005) Reprinted from Human Pathology 36, p256, Copyright 2005, with permission from Elsevier.

Figure 3

Schematic of the signaling abnormalities resulting from HER2 overexpression that are felt to contribute to tumorigenesis. HER2 overexpression results in increased HER2 containing dimers of all kinds. Increased HER2-EGFR dimers drive proliferative and invasive functions. Increased HER2 homodimers disrupt cell polarity. Increased HER2-HER3 dimers drive proliferative, survival, invasive, and metabolic functions. Increased HER2 expression results in an increase in the rare ΔHER2 isoform with more potent signaling characteristics.Several transcription factors are induced in HER2 overexpressingcells resulting in a plethora of gene expression changes.

Figure 4

Structure of the HER2 amplicon in human breast cancer. Schematic and table listing of the genes surrounding the HER2/ERBB2 locus at 17q12-q21 that are frequently co-amplified with HER2/ERBB2. Specific cancers often have larger amplicons including genes outside of this region. But amplicon mapping studies identify the above minimal common region of amplification. Reprint from Endocrine-Related Cancer 13, p39-49, copyright 2006 with permission from Society for Endocrinology and A. Kallioniemi.