The Oncogene HER2: Its Signaling and Transforming Functions and Its Role in Human Cancer Pathogenesis

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Oncogene (2007) 26, 6469–6487 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

MM Moasser

Department of Medicine and Comprehensive Cancer Center, University of California, San Francisco, CA, USA

The year 2007 marks exactly two decades since Human homologous to the v-erbB (avian erythroblastosis virus) Epidermal Growth Factor Receptor-2 (HER2) was viral oncogene and the cellular epidermal growth factor functionally implicated in the pathogenesis of human receptor (EGFR) gene (Schechter et al., 1984; Schechter breast cancer. This finding established the HER2 et al., 1985). In independent studies, an EGFR-related oncogene hypothesis for the development of some human gene was found to be amplified in a human breast cancer cancers. The subsequent two decades have brought about cell line and named HER2 (King et al., 1985). The an explosion of information about the biology of HER2 HER2 protein product was related to and had tyrosine and the HER family. An abundance of experimental kinase activity similar to EGFR (Akiyama et al., 1986). evidence nowsolidly supports the HER2 oncogene Subsequent cloning of two other related human genes hypothesis and etiologically links amplification of the and the post-genome characterization of the human HER2 gene locus with human cancer pathogenesis. The kinome completed the description of this family of molecular mechanisms underlying HER2 tumorigenesis four members (Kraus et al., 1989; Plowman et al., appear to be complex and a unified mechanistic model of 1993; Manning et al., 2002). These four members HER2-induced transformation has not emerged. Nume- are commonly referred to as EGFR (HER1, erbB1), rous hypotheses implicating diverse transforming pathways HER2 (erbB2, HER2/neu), HER3 (erbB3) and HER4 have been proposed and are individually supported by (erbB4). experimental models and HER2 may indeed induce cell The analysis of tumors from mouse models and from transformation through multiple mechanisms. Here I human cancer cells has led to the description of reviewthe evidence supporting the oncogenic function of numerous variants and mutants of HER2 and neu and HER2, the mechanisms that are felt to mediate its adherence to appropriate nomenclature is essential in oncogenic functions, and the evidence that links the order to avoid confusion. While ErbB2 is used to refer experimental evidence with human cancer pathogenesis. to the gene across both human and rodent species, Oncogene (2007) 26, 6469–6487; doi:10.1038/sj.onc.1210477; HER2 is used in reference to the human gene and gene published online 30 April 2007 product and neu is used in reference to its rodent counterparts. Table 1 lists the various HER2 and neu Keywords: HER2; HER-2; ErbB2; ErbB-2; Neu; species that have been described in the literature and the HER2/Neu nomenclature and aliases that are often used to refer to them. Each of these species is discussed in the sections below and Table 1 is provided for reference and to clarify the distinctions between these variants. Introduction

Human epidermal growthfactor receptor-2 (HER2) and neu are the human and rodent homologues of an The signaling functions of HER proteins oncogenic growthfactor receptor thatwere identiﬁed and named independently in the early 1980s from rodent The HER family proteins are type I transmembrane and human models, but soon found to be homologues of growthfactor receptors thatfunction to activate eachother(Slamon et al., 1987). The neu oncogene intracellular signaling pathways in response to extra- was initially described as a transforming oncogene cellular signals. Their structure consists of an extra- discovered in a carcinogen-induced rat brain tumor cellular ligand-binding domain, a transmembrane model (Shih et al., 1981). This gene was found to be domain and an intracellular tyrosine kinase domain (Figure 1). The function of this family is simplest in Caenorhabditis elegans where signaling is mediated by a Correspondence: Dr MM Moasser, Department of Medicine and single ligand and a single receptor and slightly more Comprehensive Cancer Center, University of California, San Francisco, complex in Drosophila where four ligands signal through UCSF Box 0875, San Francisco, CA 94143-0875, USA. a single receptor (Lacenere and Sternberg, 2000; Moghal E-mail: [email protected] Received 15 March2007; accepted 22 March2007; publishedonline 30 and Sternberg, 2003). The system is far more compli- April 2007 cated in mammalians where the functions of this family The oncogene HER2 in human cancer pathogenesis MM Moasser 6470 Table 1 Common nomenclature of HER2/neu rodent and human variants Name, aliases Description Site mutated Where found (Figure 1)

neu, c-neu, wtneu, neu Rodent cellular homologue of HER2 — In rat and mouse cells proto-oncogene neuT, neuNT, neu Rat neu containing a transmembrane domain C Discovered in a rat carcinogenesis model, oncogene, neuV664E mutation has potent transforming activity used as a potent experimental oncogene neu8142, neu8342 Rat neu containing deletion mutations in the A Found in tumors from MMTV-c-neu extracellular domain transgenic mice HER2, ErbB2, c-ErbB2 Human cellular HER2 — In human cells HER2V659E Engineered transforming mutant of human C Never found in nature, engineered for HER2, analogous to neuT experiments DHER2 Isoform of human HER2 missing one exon B Normally occurring minor isoform found wherever HER2 is expressed HER2YVMA HER2 witha kinase domain mutation and D Found in some lung cancers increased kinase activity

NH2 now known regarding the molecular basis underlying their signaling activities. Upon ligand binding to their LD1 extracellular domains, HER proteins undergo dimerization and transphosphorylation of their intracellular domains. These phosphorylated tyrosine residues dock CR1 numerous intracellular signaling molecules leading to activation of a plethora of downstream second messen- LD2 A ger pathways and crosstalk with other transmembrane B signaling pathways leading to diverse biological effects (reviewed by Prenzel et al., 2001; Yarden and Sliwkow- CR2 C extracellular ski, 2001; Barnes and Kumar, 2004; Bazley and Gullick, TM 2005). The structural bases for receptor dimerization have been coming to light in the past few years by intracellular crystollagraphic data. The extracellular domain of HER proteins can exist in a closed inhibited or an open active P D conformation. Ligand binding induces a conformational TK P change in their extracellular domain that induces the P active conformation and promotes their dimerization P and consequent transphosphorylation (Burgess et al., P P 2003). Partner selection appears to be a key determinant CT P COOH of signaling activity among HER proteins and their P signaling functions follow a distinct hierarchical order Figure 1 Structure of the HER2 and Neu proteins. The domain favoring heterodimers over homodimers. HER2 has the structure is shown on the left consisting of two ligand-binding strongest catalytic kinase activity and HER2-containing regions (LD1 and LD2), two cysteine-richregions (CR1 and CR2), a short transmembrane domain (TM), a catalytic tyrosine kinase heterodimers have the strongest signaling functions domain (TK) and a carboxy terminal tail (CT). Numerous sites of (Tzahar et al., 1996; Graus-Porta et al., 1997). The tyrosine phosphorylation within the TK and CT domains are expansion of the HER family in mammalian systems has indicated by circled P. The letters on the right point to speciﬁc areas been associated withfunctional differentiation necessi- that are altered or mutated in certain naturally occurring or experimentally induced cancers discussed in the text. (a) Site of tating interdependence rather than promoting indepen- somatic mutations found in tumors arising in MMTV-neu mice. (b) dent or redundant functions. This is exempliﬁed by Site of the 48 bp deletion in the naturally occurring human DHER2 HER2 and HER3, which are functionally incomplete isoform. (c) Site of the mutation in the neuT oncogene initially receptor molecules. Unlike the other members of the discovered in a rat carcinogen-induced tumor model and subse- family, the extracellular domain of HER2 does not pivot quently used in numerous in vitro and transgenic experimental models. (d) Site of mutations found in rare cases of human lung between active and inactive conformations and consti- cancers. tutively exists in an activated conformation (Cho et al., 2003; Garrett et al., 2003). Consistent withits constitutively active conformation, HER2 lacks ligand-binding are performed by at least 12 ligands and four receptors. activity and its signaling function is engaged by its Readers are referred to several recent excellent reviews ligand-bound heterodimeric partners (Sliwkowski, of HER family signaling and functions (Mendelsohn 2003). On the other hand HER3, unlike the other and Baselga, 2000; Olayioye et al., 2000; Prenzel et al., members, lacks adenosine triphosphate binding within 2001; Yarden and Sliwkowski, 2001; Barnes and its catalytic domain and is catalytically inactive (Sierke Kumar, 2004). While the reasons behind such multi- et al., 1997). Consistent with this, the signaling functions plicity in this system are not well understood, much is of HER3 are mediated entirely through the kinase

Oncogene The oncogene HER2 in human cancer pathogenesis MM Moasser 6471 activity of its heterodimeric partners (Kim et al., 1998). after acquisition of deletion mutations within the Even chimeric kinase-active HER3 constructs fail to extracellular juxtamembrane region that promote di- signal without hetero-partners suggesting that HER3 merization and enhanced kinase activity (Figure 1, even lacks the ability to homodimerize and is an obli- region A) (Guy et al., 1992; Siegel et al., 1994; Siegel gate heterodimerization partner (Berger et al., 2004). and Muller, 1996). The development of tumors in Although individually they are incomplete signaling MMTV-neu transgenic mice likely involves the acquisi- molecules, a large body of evidence not only establishes tion of additional genetic abnormalities, since these HER2 and HER3 as obligate partners but their complex tumors frequently have loss of heterozygosity at specific forms the most active signaling heterodimer of the genomic loci (Ritland et al., 1997; Cool and Jolicoeur, family and essential for many biologic and develop- 1999). In particular, the inactivation of p53 is descrip- mental processes (Sliwkowski et al., 1994; Horan et al., tively and etiologically linked with neu-induced mouse 1995; Wallasch et al., 1995b; Tzahar et al., 1996; Britsch mammary tumors (Li et al., 1997). Additional transgenic et al., 1998; Keely and Barrett, 1999; Vartanian et al., models demonstrate that overexpression or activation of 2000; Goodearl et al., 2001; Vijapurkar et al., 2003). neu is tumorigenic in other tissues as well, including The HER proteins are widely expressed and function- skin, biliary tract and prostate (Table 2). The tumori- ally important in non-hematopoietic tissues (Real et al., genic function of activated neu has also been confirmed 1986; Press et al., 1990). They are each essential in in two rat models by luminal retroviral infection (Wang mammalian development and gene disruption models et al., 1991). The transforming functions of neu require in mice reveal that they are critically involved in its tyrosine kinase activity as demonstrated by kinase- the development of multiple organ systems, including the inactivating mutational studies (Weiner et al., 1989a). brain, skin, lung and gastrointestinal tract (Gassmann The rodent data amounts to a body of highly consistent et al., 1995; Lee et al., 1995; Miettinen et al., 1995; and indisputable evidence that activation of neu is Sibilia and Wagner, 1995; Threadgill et al., 1995; tumorigenic. The MMTV-neu mice have become the Erickson et al., 1997; Riethmacher et al., 1997; Britsch workhorse model of HER2 tumorigenesis in vivo. et al., 1998; Sibilia et al., 1998; Morris et al., 1999). Their functional importance in adult mammary gland development escapes analysis in these germline deletion Transformation by HER2 models due to embryonic lethality but is nicely demon- The data with regards to human HER2 are also strated by alternative models that inactivate EGFR or compelling, however, there appears to be significant HER2 in pubertal mammary tissue (Xie et al., 1997; differences between the rodent and human genes. While Andrechek et al., 2005). rodent neu appears to require mutational activation for tumorigenicity, human HER2 appears to hold tumorigenic potential through overexpression alone. An The transforming potential of HER2 and neu engineered mutation within the transmembrane region of HER2 (Figure 1, region C) does increase its kinase Transformation by neu and transforming activities similar to neu, however, this The data supporting the transforming potential of mutation does not appear to occur spontaneously human HER2 and rodent neu are irrefutable. The (Segatto et al., 1988). Overexpression of HER2 in rodent neu oncogene was initially identified in a screen NIH3T3 or NR6 mouse fibroblasts induces cell trans- for oncogenes using a rat carcinogen-induced tumor formation and tumorigenic growth(Di Fiore et al., model and shown to transform NIH3T3 cells (Shih 1987; Hudziak et al., 1987; Chazin et al., 1992). et al., 1981; Schechter et al., 1984). The neu oncogene Overexpression of HER2 in MCF-7 breast cancer cells also transforms mammary epithelial cells in vitro increases their invasiveness and tumorigenicity (Benz (Brandt et al., 2001). After cloning of the normal c-neu et al., 1992). Overexpression of HER2 in human allele, it was determined that transforming function in mammary epithelial cells induces proliferative advan- the neu oncogene was conferred by a point mutation tage, transformed characteristics, tumorigenic growth within the transmembrane domain resulting in a V664E- and in three-dimensional (3D) models induces proli- mutated protein named neuT (Bargmann et al., 1986) ferative and antiapoptotic changes that mimic early (Figure 1, region C). The V664E mutation promotes stages of epithelial cell transformation (Muthuswamy receptor dimerization and enhanced tyrosine kinase et al., 2001; Woods Ignatoski et al., 2003). Transgenic activity (Weiner et al., 1989b). Numerous mouse expression of the human HER2 cDNA in mouse transgenic models have confirmed the role of this mammary breast tissue induces metastatic mammary oncogene in tumorigenesis. The activated neu oncogene tumors similar to neu (Finkle et al., 2004). However, in (neuT) expressed in mice mammary tissue (MMTV-neuT this cross-species MMTV-HER2 transgenic model, the mice) induces adenocarcinomas. This appears as a resulting mouse tumors have frequent deletion muta- single-step whole-gland transformation or in a more tions within the extracellular domain of the HER2 typical stochastic tumor formation in different back- transgene similar to that seen with MMTV-neu mice. grounds (Muller et al., 1988; Bouchard et al., 1989). The However, neither mutations within the transmembrane c-neu protooncogene overexpressed in mammary tissue domain (analogous to neuT, see Figure 1, region C) or of mice (MMTV-neu mice) also induces tumor forma- the extracellular domain (analogous to neu8142/ tion, although in the majority of tumors, this occurs neu8342, Figure 1, region A) of HER2 have ever been

Oncogene The oncogene HER2 in human cancer pathogenesis MM Moasser 6472 Table 2 Reported mouse transgenic models of HER2/neu Reference Promoter Gene Phenotype

Muller et al. (1988) MMTV neuT transgene Early, multiple mammary tumors by 3 months, short survival Bouchard et al. (1989) MMTV neuT transgene Mammary tumors stochastically, 5–10 months Guy et al. (1992) MMTV c-neu transgene Mammary tumors stochastically, 4–12 months, frequent lung metastases Andrechek et al. (2000) Endogenous neuT knock-in Late mammary tumors, 12–17 months, with transgene ampliﬁcation Weinstein et al. (2000) Murine neu c-neu transgene Abnormal involution, focal mammary abnormalities in multiparous females, 1–2 years Weinstein et al. (2000) Murine neu neuT transgene Abnormal involution, some late mammary tumors in multiparous females, 14 months Finkle et al. (2004) MMTV human HER2 Multiple mammary tumors, 7 months, some lung mets transgene Moody et al. (2002) MMTV-rtTA / TetO neuT transgene Rapid mammary tumors within 6 weeks and frequent lung mets, regress without dox Xie et al. (1998) Human Keratin 14 neuT transgene Severe hyperplastic lesions of skin , hair follicles, esophagus, perinatal lethal Bol et al. (1998) Bovine keratin 5 neuT transgene Severe hyperplastic lesions of skin, esophagus, papillomas, early death Kiguchi et al. (2000, Bovine keratin 5 c-neu transgene Hyperplasia, allopecia, papillomas, skin carcinomas, biliary 2001) carcinomas, survive 6–12 months Xie et al. (1999) K14-rtTA-TetRE neuT transgene Rapid dox induction of hyperplastic lesions in skin, hair ollicles, esophagus, regress without dox Li et al. (2006) Probasin neuT transgene Prostatic intraepithelial neoplasia and invasive prostate cancer, 1–2 years

reported in naturally occurring human cancers and defines a subtype of breast cancer not a later stage of it. despite these experimentally acquired mutations, human This is further underscored by gene expression profiling breast cancers appear to be always characterized by studies that show that HER2 amplified breast cancers overexpression of wild-type HER2. Interesting theories comprise a specific disease subset witha unique regarding this discrepancy have been proposed and are molecular portrait and this portrait is maintained during reviewed below in the section concerning DHER2. progression to metastatic disease (Perou et al., 2000; Weigelt et al., 2005). HER2 amplified breast cancers have biologic characteristics that distinguish them from HER2 overexpression in human cancer other types of breast cancers. These include increased The relevance of the experimental data to human disease sensitivity to certain cytotoxic chemotherapeutic agents, is supported by a substantial body of clinical data. resistance to certain hormonal agents and increased Overexpression of the HER2 protein, either through propensity to metastasize to the brain (Ross et al., 2003; gene amplification or through transcriptional deregula- Gabos et al., 2006). HER2 overexpression and amplifi- tion is seen in approximately 25–30% of breast and cation is also seen in subsets of gastric, esophageal and ovarian cancers and confers worse biological behavior endometrial cancers, also associated withworse disease (Slamon et al., 1989). Initial conflicting reports regard- (Mimura et al., 2005; Morrison et al., 2006; Yano et al., ing the prognostic relevance of HER2 were resolved 2006) and also seen rarely in cancers of the oropharynx, with improved methodologies and the overwhelming lung and bladder (Hirsch et al., 2002; Khan et al., 2002; data now confirms this initial landmark genetic-biologic Latif et al., 2003). The etiologic role of HER2 over- finding (nicely reviewed by Ross et al., 2003). Breast expression in diseases other than breast cancer remain to cancers can have up to 25–50 copies of the HER2 gene be defined. and up to 40- to 100-fold increase in HER2 protein expression resulting in up to 2 million receptors expressed at the tumor-cell surface (Venter et al., 1987; HER2 kinase domain mutations in human tumors Kallioniemi et al., 1992; Lohrisch and Piccart, 2001) Large-scale resequencing efforts have only begun to (Figure 2). Evidence suggests that HER2 amplification is screen human tumors for somatic mutations. Somatic an early event in human breast tumorigenesis. HER2 mutations within the HER2 kinase domain have been amplification is seen in nearly half of all in situ ductal described in a small subset of lung cancers, predomi- carcinomas without any evidence of invasive disease nantly in Asian populations, and very rarely in gastric, (Liu et al., 1992; Park et al., 2006). HER2 status is colorectal and breast cancers (Figure 1, region D) maintained during progression to invasive disease, nodal (Stephens et al., 2004; Shigematsu et al., 2005; Lee metastasis and distant metastasis (Tsuda et al., 2001; et al., 2006). Muchless is currently known about the Latta et al., 2002; Carlsson et al., 2004; Park et al., biology of these rare HER2 mutations. At least one of 2006). Therefore, although HER2 amplified breast these mutations has been shown to enhance HER2 cancers appear to have a higher propensity for progres- kinase activity and increase its transforming efficiency sion and worse prognosis compared withnon-amplified (Wang et al., 2006). Although numerous mouse models breast cancers, the amplification is an early event and have established the tumorigenic potential of neu

Oncogene The oncogene HER2 in human cancer pathogenesis MM Moasser 6473 tumorigenesis is overwhelming and was reviewed above. The data regarding the pathways that mediate, that are required for, and that cooperate with HER2-induced transformation are muchmore diverse and most likely HER2 induces transformation through a number of signaling pathways. The relative contribution of these pathways to tumorigenesis are difﬁcult to know. The mechanisms and pathways for which there is signiﬁcant evidence are reviewed below and are schematically depicted in Figure 3.

Figure 2 FISH analysis of HER2 amplification. (a) Human breast cancer specimen hybridized with a HER2 gene probe (in green) and Overactivity vs overexpression a chromosome 17 centromeric probe (in red) showing significantly In the simplest mechanistic model, HER2 induces increased HER2 gene copy number compared withthechromosome 17 control (Hicks and Tubbs, 2005). Reprinted from Human transformation through increased kinase activity and Pathology 36, p256, Copyright 2005, with permission from Elsevier. overphosphorylation of itself and cellular substrates. In this model, the sole consequence of overexpression is to increase cellular HER2 activity. But a limitation of this through overexpression, HER2 mutation in lung cancers model is that it fails to explain why in human cancers is not known to be associated withoverexpression or HER2 activity is always elevated through overexpres- gene amplification. As such, a tumorigenic function of sion, and mutational activation of HER2, analogous to this mutated HER2 cannot be presumed and awaits the rodent neuT, is never seen in human breast cancers. One appropriate transgenic mouse models for analysis. In explanation that has been offered is that neu can be breast tissue, activated neu is not by itself transforming activated through a single base pair mutation, whereas and requires amplification and overexpression to induce the analogous activation of HER2 requires a two base tumorigenesis (Andrechek et al., 2000). Muchof the pair mutation, making this much less likely to occur data discussed in this review pertains to the over- spontaneously in the human gene. However, a more expression model of HER2 transformation. Our under- plausible explanation has been that increased expression standing of the biology of kinase-domain-mutated of HER2 is an essential aspect of its transforming HER2 is still in its infancy and ongoing studies in this function. This presents a more complex model of area will undoubtedly shed further light on the transformation, but there is substantial evidence to biological characteristics of this HER2 mutant, its role support it. While high-level expression of neu or neuTis in tumorigenesis, and its similarities or differences with tumorigenic in transgenic models, converting the en- overexpressed HER2. dogenous neu to neuT by knockin methodology leads to architectural distortion but is insufficient to induce HER2 polymorphism in humans tumorigenesis (Andrechek et al., 2000). These mice do Although somatic mutations in the transmembrane eventually develop tumors withlong latency, however, domain of HER2 analogous to the neu oncogene have these tumors are characterized by amplification and neu not been seen in human tumors, polymorphism in the overexpression of the mutant allele supporting transmembrane domain of HER2 (Figure 1, region C) the hypothesis that overexpression is mechanistically has been described. In particular, the I665V variant of required for transformation by HER2. A number of HER2 has increased potential for dimerization and mechanistic models are able to propose how over- signaling (Fleishman et al., 2002). This has led some expression of HER2 can disrupt signaling and promote investigators to propose that the I665V allele of HER2 tumorigenic functions. Overexpression of HER2 can may confer increased susceptibility to breast cancer. change the composition of HER family dimers, sig- Although an initial large study indeed found such an nificantly increasing HER2-containing heterodimers association withbreast cancer risk, several subsequent and HER2 homodimers. Evidence discussed below studies have shown conflicting results with the majority suggests that these increases can deregulate cell polarity of them showing no risk associated with the I665V and cell adhesion. In addition, evidence discussed below genotype (Xie et al., 2000; Montgomery et al., 2003; also shows that HER2-containing dimers have pro- Benusiglio et al., 2005). The preponderance of evidence longed signaling activity and evade signal attenuation at this time does not appear to support an association increasing signaling potency. Increased total expression between HER2 polymorphism and breast cancer risk, of HER2 carries withit an increase in expression of although this continues to be debated. subsets of HER2 including nuclear HER2 and the rare DHER2 isoform, and the increase in each of these may be functionally relevant to cell transformation. These are also discussed individually below. Mechanisms of HER2-mediated tumorigenesis The recent discovery that rare types of lung cancers have HER2 kinase domain mutations that confer The evidence that increased expression and activity increased kinase activity without overexpression may of neu or HER2 induces cell transformation and be inconsistent withtheoverexpression model. But it is

Oncogene The oncogene HER2 in human cancer pathogenesis MM Moasser 6474 MUC4

S EGFR HER3 HER2 HER2 HER2 HER2 HER2 HER2 HER2 HER2 HER2 HER2 HER2 HER2

src

increased EGFR increased increased HER3 increased HER2 heterodimer signaling homodimer signaling heterodimer signaling

PI3K Ras PAR6 PI3K aPKC PLC Akt

proliferation survival invasion CyclinD1 / p27 loss of polarity metabolism G1/S deregulation invasion

ETS COX2 CXCR4 transcription factors

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 DHER2 isoform withmore potent signaling characteristics. Several transcription factors are induced in HER2-overexpressing cells resulting in a plethora of gene expression changes.

too soon to challenge this model since very little is yet Waterman et al., 1998). Therefore, HER2 overexpres- known about the biology of the kinase domain-mutated sion results in increased EGFR membrane expression HER2. Studies forthcoming in the coming years will and activity (Huang et al., 1999; Wang et al., 1999; determine whether this HER2 mutant is transforming Hendriks et al., 2003b). But it seems unlikely that HER2 without overexpression and establish its role in the requires EGFR for its transforming function, since evolution of lung cancer. A unified model of HER2 HER2 also transforms NR6 fibroblasts, which lack transformation that also explains why HER2 is deregu- EGFR expression (Chazin et al., 1992). The analogous lated through overexpression in breast and ovarian dispensibility of EGFR in epithelial models of HER2 cancers but through mutation in lung cancers is transformation has not been specifically demonstrated. impossible to propose at this time and must await a Overall, compared with other members of the family, muchbetter understanding of its biology in lung HER2 is least subject to inactivating mechanisms and its cancers. recruitment into heterodimeric-signaling complexes leads to prolonged signaling. As such, HER2-overexpressing cells have significantly prolonged activation Deregulation of HER family signaling dynamics of downstream mitogen-activated protein kinase At the lateral level HER2 overexpression causes (MAPK) and c-jun following stimulation withEGFR increased HER2 heterodimerization with EGFR and or HER3 ligands compared withlow HER2 cells HER3 (Karunagaran et al., 1996; Hendriks et al., 2003a) (Karunagaran et al., 1996). (Figure 3). This interferes with the endocytic regulation of EGFR. EGFR is unique among the HER family, in that, it undergoes endocytic degradation after ligand- Signaling through HER3 and downstream PI3K/Akt mediated activation and homodimerization, in contrast The functional role of HER3 is much better established. to the other members of the family, which undergo HER3 is widely expressed in breast cancers (Lemoine endocytic recycling (Baulida et al., 1996). EGFR-HER2 et al., 1992). Heregulin regulates HER2 through heterodimers similarly evade endocytic degradation in coexpressed HER3 (Wallasch et al., 1995b). HER2 favor of the recycling pathway and have increased and HER3 cooperatively induce transformation and in signaling duration and potency (Lenferink et al., 1998; fact HER3 is an obligate partner in HER2-induced

Oncogene The oncogene HER2 in human cancer pathogenesis MM Moasser 6475 transformation (Alimandi et al., 1995; Holbro et al., transforming potency similar to the mutated neu gene 2003). Tumors from MMTV-neu mice have increased (Kwong and Hung, 1998; Siegel et al., 1999). This HER3 expression and phosphorylation and elevated deletion removes cysteine residues in neu and in HER2, HER3 expression is similarly seen in HER2-overexpres- disrupting the disulfide bond structure of the proteins sing human tumors (Siegel et al., 1999). The most and leaving unpaired cysteine residues available for important oncogenic signaling function of the HER2– intermolecular bonding. Experimental models have HER3 complex appears to be activation of the confirmed that DHER2 has increased transforming phosphatidylinositol 3-kinase (PI3K)/protein kinase B activity compared withwtHER2 in several models, (Akt) pathway (figure 3). HER2 lacks binding sites for including in vitro and transgenic models, and DHER2 the p85 subunit of PI3K, whereas HER3 has seven p85- has significantly higher dimerization promoted by binding phosphotyrosine-containing motifs (Prigent and intermolecular disulfide-bond stabilization, and signifi- Gullick, 1994; Soltoff et al., 1994; Schulze et al., 2005). cantly increased tyrosine phosphorylation compared Growthfactor-mediated activation of PI3K and Akt by withwtHER2 (Kwong and Hung, 1998; Siegel et al., HER2 is mediated specifically through phosphorylation 1999; Castiglioni et al., 2006). Although the activated of HER3 (Fedi et al., 1994; Soltoff et al., 1994; Hellyer DHER2 transcript is a normal byproduct of HER2 et al., 2001). Cell transformation by overexpressed transcription, its significant increase in HER2-amplified HER2 is also associated withincreased HER3 phos- tumors has been proposed as a mechanism underlying phorylation and activation of PI3K/Akt signaling HER2 tumorigenesis. DHER2 transcripts have been (Alimandi et al., 1995; Wallasch et al., 1995a; Ram detected in a majority of breast tumors and normal and Ethier, 1996; Holbro et al., 2003; Tokunaga et al., breast tissue and cell lines and reported by two groups to 2006). Tumors from MMTV-neu mice also have comprise 4–9% of total HER2 transcripts (Siegel et al., activation of PI3K signaling (Amundadottir and Leder, 1999; Castiglioni et al., 2006). This hypothesis of HER2- 1998). This is corroborated by clinical studies, which induced tumorigenesis implies that the presence of the show the frequent activation of Akt in HER2-over- naturally occurring DHER2 obviates the need for expressing tumors (Zhou et al., 2004; Tokunaga et al., human HER2 to undergo mutational activation. The 2006). The existing data strongly suggest that the MMTV-human HER2 mouse transgenic model is transactivation of HER3 and downstream PI3K/Akt seemingly consistent with this. In this model, mouse seems to be a critical tumorigenic function of over- mammary tumors are induced by overexpression of the expressed HER2. This is consistent with numerous other human HER2 cDNA, which does not have a DHER2 lines of evidence that highlight a central role for Akt in transcriptional by product associated withit (Finkle tumorigenesis. Akt functions in the crossroads of et al., 2004). Interestingly, the majority of tumors in this multiple signal transduction pathways that regulate model have acquired deletion mutations of the juxta- numerous cellular functions critically important for membrane region of the human HER2 transgene similar cancer cells, including cell proliferation and survival, to the neu transgenic model. This is consistent with the cell size and response to nutrient availability, glucose hypothesis that there is a selection pressure for this metabolism, epithelial–mesenchymal transition and cell mechanism of activation, whether it is through gene invasiveness, genome stability and angiogenesis. The mutation or whether it is through increased expression critical function of Akt in cancer is now widely of DHER2. More definitive proof of the causative role recognized but will not be discussed in this review. of DHER2 awaits the development of experimental Readers are referred to a number of excellent recent reagents that selectively target and inactivate the reviews of this topic ((Testa and Bellacosa, 2001; DHER2 isoform. Vivanco and Sawyers, 2002; Luo et al., 2003; Paez and Sellers, 2003) and the entire Oncogene vol. 24; issue 50 (11/14/2005)). The abundance of data reviewed above Role of Src kinases suggests that HER2-induced tumors activate Akt Since HER family proteins signal predominantly through HER3 and PI3K. through the recruitment of proteins to their tyrosine phosphorylated residues, their transforming functions could be in large part mediated through these interact- Alternative HER2 transcript ing proteins, in particular SH2 domain-containing The fact that deletion mutations in the extracellular proteins. Evidence suggests that src kinases are im- region of the receptor seen in neu-overexpressing mouse portant second messengers of HER2. Src kinases are mammary tumors are not seen in human tumors has potently transforming and tumorigenic when constitu- produced a dilemma and an interesting hypothesis to tively activated, and their activation is seen in many resolve it. A naturally occurring but rare human HER2 human tumor types, including breast cancers with or RNA transcript has been cloned that is alternatively without HER2 overexpression (Ottenhoff-Kalff et al., spliced and lacks a single 48 bp coding exon resulting 1992; Belsches-Jablonski et al., 2001; Reissig et al., in the in-frame deletion of 16 amino acids from the 2001). An association between src activation and HER2 juxtamembrane region overlapping withthearea of overexpression has been reported in pre-invasive carci- deletion mutations seen in neu-induced tumors. This nomas of the breast (Wilson et al., 2006). Mammary alternative HER2 protein, named DHER2, has increased tumors that arise in MMTV-neu transgenic mice have ligand-independent signaling activity and increased activation of c-src and c-yes (Muthuswamy et al., 1994;

Oncogene The oncogene HER2 in human cancer pathogenesis MM Moasser 6476 Muthuswamy and Muller, 1995a). In vitro models although the basal membrane is preserved and invasive corroborate a direct link between src and HER2. features are not induced (Muthuswamy et al., 2001). Transformation of mammary epithelial cells by HER2, Activated HER2 disrupts apical-basal polarity through but not by H-Ras, results in the activation of c-src its interaction withcomponents of thePar polarity (Sheffield, 1998). Therefore, it seems plausible that src complex including PAR6 (partition protein 6) and functions downstream of oncogenic HER2. But a clear aPKC (atypical protein kinase C) (Aranda et al., mechanistic model of how HER2 activates src and proof 2006). On the other hand, the experimental hetero- that this activation is essential for tumorigenesis has not dimerization of HER2 withEGFR promotes the yet emerged. Src directly interacts with HER2 within the invasive phenotype mediated through pathways, includ- HER2 catalytic domain (Muthuswamy and Muller, ing PI3K, Ras and PLCg (phospholipase Cg) (Zhan 1995b; Belsches-Jablonski et al., 2001; Kim et al., et al., 2006). These studies were carried out using 2005). It has been suggested that HER2 activates src engineered synthetic ligand-activated constructs that can through increasing its expression and stability, or by discriminate between the functions of homodimers and directly phosphorylating src on tyr215 in its SH2 heterodimers of HER2 in cells grown in 3D models domain (Vadlamudi et al., 2003; Tan et al., 2005a). (Muthuswamy et al., 1999). It is inferred from these Inhibition of src kinases in HER2-overexpressing studies that overexpressed HER2 in cancers, through tumors cells using src-selective tyrosine kinase inhibitors increased HER2 homodimers and HER2-EGFR hetero- has produced different phenotypes including the selec- dimers mediates the loss of polarity and deregulated cell tive inhibition of invasive and prometastatic charac- adhesion typical of epithelial cancers (Figure 3). teristics in one report and total growthinhibition and apoptosis in another report (Belsches-Jablonski Promoting the invasive phenotype et al., 2001; Tan et al., 2005b). A specific function in Multiple downstream signals may be mediating the promoting migration, invasion and metastasis would be invasive phenotype associated with HER2 overexpres- highly consistent with the known functions of src in sion in tumor cells. Downstream signals that have been regulating focal adhesions and integrin signaling, and implicated in the invasive phenotype include activation regulation of the actin cytoskeleton. Consistent with of PI3K (Ignatoski et al., 2000), PKC-a and src (830), this, HER2-mediated activation of c-src in epithelial focal adhesion kinase (Ignatoski et al., 2000; Benlimame cells results in loss of polarity, disruption of cell–cell et al., 2005), downregulation of a4 integrin (Woods adhesions and anchorage-independent growth (Shef- Ignatoski et al., 2003), induction of b4 integrin field, 1998; Kim et al., 2005). In contrast to a down- (Gambaletta et al., 2000), and transforming growth stream function of c-src, recent reports show c-src factor-b (Seton-Rogers et al., 2004). The functional can also function upstream of HER2. C-src enhances significance of b4 integrin in particular has recently been HER2–HER3 dimerization and increases their auto- established in genetic models. HER2 physically interacts and trans-phosphorylations and signaling activities with b4 integrin (Falcioni et al., 1997) and tumors (Ishizawar et al., 2006). C-src also phosphorylates arising in MMTV-neu mice have delayed onset and HER2 at tyr877 within the activation loop of the kinase reduced invasion and metastases if b4-integrin signaling domain and increases the kinase activity of HER2 (Xu is disrupted genetically (Guo et al., 2006). Furthermore, et al., 2007). These data imply that, in addition to ex vivo studies demonstrated that the proliferative functioning downstream, src kinases may also function phenotype of neu is mediated through c-jun and the upstream or midstream of the transforming functions disruption of cell adhesions is mediated through STAT3. of HER2 (Figure 3). A multilevel involvement of src kinases would make them critical enhancers of HER2 driven tumorigenesis. Genetic crosses to prove an Cell cycle deregulation essential role of src in neu-induced mammary tumori- Deregulation of cell cycle control, in particular G1/S genesis have been difficult to do owing to the poor checkpoint control, leads to uncontrolled proliferation health and survival of src null mice. and is a hallmark of many cancers. The two cell cycle regulators that have emerged as downstream targets of oncogenic HER2 are cyclin D1 and p27 (Figure 3). Disruption of cell adhesion and cell polarity HER2 overexpression in breast epithelial cells dere- A hallmark of many epithelial cancers is the loss of cell gulates G1/S control through upregulation of cyclin D1, polarity and cell adhesion. Recent evidence demon- E and cdk6, and degradation of p27 (Timms et al., strates that deregulated HER2 signaling can disrupt cell 2002). Human tumor studies have only compared cyclin polarity and cell adhesion. HER2, by virtue of its D1 expression among different breast cancers and have interaction withERBIN (ErbB2 interacting protein), found no significant increase in cyclin D1 expression in normally localizes to the basolateral surface of epithelial HER2-overexpressing tumors compared withtheirnon- cells where it likely mediates crosstalk with ligand- overexpressing counterparts (Loden et al., 2003; Yang secreting stromal cells (De Potter et al., 1989; Borg et al., et al., 2004; Ahnstrom et al., 2005). It remains possible 2000; Shelly et al., 2003). The experimental homodimeri- that cyclin D1 is widely overexpressed in breast cancers zation and activation of HER2 leads to disruption of and it occurs through other pathways in tumors tight junctions, loss of cell polarity and proliferative without HER2 overexpression. Consistent with this, a disarray in breast epithelial cell acinar structures, necessary but not rate-limiting role of cyclin D1 for

Oncogene The oncogene HER2 in human cancer pathogenesis MM Moasser 6477 HER2-induced tumorigenesis has been shown in trans- The role of HER2 neighbors genic models. MMTV-neu mice have almost complete While all the experimental preclinical models are protection from tumor formation in a cyclin D1-null generated by specific overexpression of the singular background (Lee et al., 2000; Yu et al., 2001). With HER2 gene, the overexpression of HER2 in naturally prolonged intervals, hyperplastic lesions eventually occurring breast cancers is almost always due to develop owing to cyclin E compensation (Bowe et al., amplification of a segment of chromosome 17 at 2002). Consistent withtherequisite role of cyclin D1, its 17q12–q21 that contains many genes in addition to catalytic partner cdk4 is also required for tumorigenesis HER2. Therefore, the human disease involves a more in MMTV-neu mice (Reddy et al., 2005). Other lines of complex genetic basis than the experimental models evidence also corroborate the hypothesis that HER2 provide. The effort to identify the genes co-amplified induces transformation through increased cyclin D1/ with HER2 in human breast cancer has been greatly cdk4 activity. Expression of the cyclin D1/cdk4 inhibitor facilitated by modern techniques and access to the p16 in breast tissue also protects against tumors in human genome database. The structure of the HER2 MMTV-neu mice (Yang et al., 2004). amplicon has now been characterized using a variety of HER2 regulates p27 through multiple mechanisms techniques including Southern blotting, fluorescence that regulate its localization and its proteolysis. Akt is in situ hybridization (FISH) and comparative genomic activated in HER2-amplified breast cancers (reviewed hybridization, as well as looking for highly expressed above) and activated Akt phosphorylates p27 inhibiting neighboring genes by reverse transcription–polymerase its function by excluding it from the nucleus (Liang chain reaction and microarray expression analyses et al., 2002; Shin et al., 2002; Viglietto et al., 2002). ((Kauraniemi et al., 2001; Luoh, 2002) and reviewed Several clinical studies have also established that HER2- by (Kauraniemi and Kallioniemi, 2006). The HER2 overexpressing breast cancers have reduced p27 expres- amplicon is relatively small and fairly constant among sion compared withothertypes of breast cancers many breast tumors and spans a minimal region of (Newman et al., 2001; Loden et al., 2003; Spataro approximately 280 kb centered around the HER2 locus et al., 2003). HER2 mediates p27 degradation likely (Kauraniemi et al., 2003) (Figure 4). This region through mechanisms that involve MAPK (Yang et al., contains 10 transcribed genes, of which six are over- 2000; Donovan et al., 2001; Lenferink et al., 2001). expressed in tumors as a result of amplification of the Consistent witha functional role for p27, HER2-induced region, suggesting that they may be the biologically cell transformation can be inhibited by forced expression relevant genes. These include HER2, GRB7, MLN64, of p27 (Yang et al., 2001). The cell cycle function of PNMT, MGC9753 and MGC14832. GRB7 is an SH2- oncogenic HER2 is likely mediated specifically through its containing adaptor protein and is functionally linked regulation of cyclin D1 and p27, since other G1/S defects with HER2 as it is known to bind phosphorylated suchas loss of p16 or Rb are not seen in HER2-amplified HER2 and mediate aspects of cell migration (Janes breast cancers, whereas they are common in other types of et al., 1997). MLN64 is a late endosomal membrane breast cancer (Yang et al., 2004). protein that binds sterols and is felt to be involved in cholesterol transport (Alpy and Tomasetto, 2006). PNMT (phenylethanolamine N-methyltransferase) is a The role of transmembrane mucins catecholamine biosynthetic enzyme and is unlikely to be While in the simplest scenario, HER family receptor important for HER2 tumorigenesis. The functions of the interactions are driven by their affinities for each other, hypothetical proteins MGC9753 and MGC14832 are there is evidence that other transmembrane proteins can currently unknown. In the mouse knockin model of facilitate their interactions. HER2 stably interacts with HER2 tumorigenesis that occurs through spontaneous the membrane mucin Muc4. The interaction is mediated gene amplification, the mouse tumor HER2 amplicon is through one of two EGF-like domains in Asialoglyco- highly similar to the human breast cancer amplicon and protein-1 (ASPG-1), the membrane-associated subunit contains the same genes, consistent with the hypothesis of Muc4 and may play a role in regulating the polar that genes in addition to HER2 are selected for in the localization of HER2 (Carraway et al., 1999; Ramsauer amplification event (Hodgson et al., 2005). Studies to et al., 2003). The experimental induction of Muc4 determine the functional relevance of these genes in expression in cells lacking Muc4 leads to increase cell HER2-driven tumorigenesis are ongoing. surface retention of HER2 and HER3 and increased HER2–HER3-signaling activity (Funes et al., 2006) (Figure 3). The evidence that Muc4 potentiates HER2 HER2-linked genomic abnormalities signaling has led to the hypothesis that it may promote In addition to the genes directly located within the HER2 tumorigenic signaling even in tumors that do not 17q12 HER2 amplicon, HER2-amplified breast cancers overexpress HER2. Consistent with this hypothesis, often have numerous other genomic alterations that are increased expression of Muc4 is associated withworse characteristic of this tumor type and much less common prognosis in several types of cancer (Shibahara et al., in breast tumors without HER2 amplification. These 2004; Saitou et al.,2005;Tamadaet al., 2006; Tsutsumida include amplifications in 17q22–24, just distal to the et al., 2006). Further analysis of this hypothesis awaits HER2 amplicon as well as amplifications in 20q and models that more definitively demonstrate the role of deletions in 18q (Isola et al., 1999). These areas may also Muc4 in promoting tumorigenic HER2 function. contain genes that through gain or loss of function could

Oncogene The oncogene HER2 in human cancer pathogenesis MM Moasser 6478

SYMBOL ALIAS DESCRIPTION Start bp position NEUROD2 Neurogenic differentiation 2 35014575 PPP1R1B DARPP-32 Protein phosphatase 1, regulatory (inhibitor) subunit 1B 35036705 STARD3 MLN64 START domain containing 3 35046938 TCAP Titin-cap (telethonin) 35075125 PNMT Phenylethanolamine N-methyltransferase 35078033 PERLD1 MGC9753 per1-like domain containing 1 35080902 ERBB2 HER2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 35109922 C17 or f37 MGC14832 Chromosome 17 open reading frame 37 35138937 GRB7 Growth factor receptor-bound protein 7 35147744 ZNFN1A3 Zinc finger protein, subfamily 1A, 3 (Aiolos) 35174724

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.

cooperate to establishthebiology of HER2-amplified transcriptional function, a small percentage of cellular tumors. The topoisomerase IIa (TOP2A) gene on 17q21 HER2 is seen in nuclei and DNA binding and is frequently co-amplified withHER2 and may explain transcriptional activation of at least one promoter has why HER2 overexpressing breast cancers are particu- been reported (Wang et al., 2004). A transcriptional larly sensitive to treatment withtopoisomerase inhibi- function inherent in HER2 significantly widens the tors (Mano et al., 2006). realm of mechanisms by which overexpressed HER2 can Of particular interest, the PTPN1 gene encoding mediate tumorigenic functions. The transcriptional protein tyrosine phosphatase 1B (PTP1B) on 20q13 is function of HER2 is clearly not the principal mechanism often amplified in HER2-amplified breast cancers underlying its transforming functions, since kinase (Tanner et al., 1996). Although tyrosine phosphatases function is essential for neu-induced transformation frequently play negative feedback roles in growthfactor (Weiner et al., 1989a). But transcriptional targets may receptor signaling, the frequent amplification and over- be enhancing its transforming functions. So far the expression of PTPN1 in HER2-amplified tumors has led cyclooxygenase-2 (COX-2) gene has been reported as a to the hypothesis that it may have a tumor-promoting direct target of HER2. However, the upregulation (and function in these tumors. Consistent with this hypo- downregulation) of numerous other genes has been thesis, tumor formation in MMTV-neu mice is signifi- described in HER2-amplified tumors and in fact these cantly delayed or prevented in the PTPN1-null tumors have a gene expression profile unique to HER2- background (tires-Alj and Neel, 2007). The molecular amplified breast cancers (Perou et al., 2000). Many of mechanisms mediating the supportive tumorigenic role these genes are likely consequences of HER2 over- of PTP1B remain to be worked out. expression, although some may be directly driven by HER2 transcriptional function. The pathways that current evidence suggests are functionally relevant are reviewed below. The role of many other genes remains Transcriptional targets of HER2 to be defined. While the function of HER proteins as transmembrane growthfactor receptors is well understood and innu- Induction of COX-2 merable lines of evidence are consistent withits growth The inducible prostaglandin synthase COX-2 is over- factor signaling function, a nuclear function as a expressed in HER2-amplified breast cancers (Subbara- transcription factor has also been proposed. In early maiah et al., 2002). HER2 directly regulates COX-2 two-hybrid screens for Neu interacting proteins, the expression through transcriptional induction (Vadlamudi cytoplasmic domain of Neu used as a bait was et al., 1999; Wang et al., 2004). COX-2 knockout mice unexpectedly found to have transcriptional transactivat- are impaired in their ability to support MMTV-neu- ing activity (Xie and Hung, 1994). Consistent witha induced mammary tumorigenesis (Howe et al., 2005).

Oncogene The oncogene HER2 in human cancer pathogenesis MM Moasser 6479 Interestingly, this phenotype seems to be related to systems (see above), its suitability as a drug target impaired angiogenic signaling. Whether this is due to depends on whether clinically advanced tumors continue defective tumor cell angiogenic signaling or host to dependent on HER2 for survival and progression. angiogenic signaling is not currently defined. As such, This dependency, recently described as oncogene addic- the role of tumor COX-2 in HER2-induced transformation, implies that such cancers can be effectively treated tion remains to be defined. and possibly cured with drugs that inactivate the oncogene product (Weinstein, 2002). Alternatively, Induction of CXCR4 genomic instability can lead to the mutational activation HER2 induces the expression of the chemokine receptor of additional pathways that could compensate for the CXCR4 in transfection models and indeed increased pharmacologic inactivation of the tumor-initiating expression of CXCR4 is seen in HER2-overexpressing oncogene making suchan oncogene less effective as a breast cancers (Li et al., 2004). Chemokine receptors drug target. have been functionally linked with the metastatic properties of breast cancers (Muller et al., 2001) leading HER2 knockdown models to the hypothesis that the prometastatic properties of Since the identification of HER2 as an oncogene in HER2-overexpressing tumors may be mediated through human tumors, numerous approaches have been under- the increased expression of relevant chemokine recep- taken to demonstrate the dependence of HER2-over- tors. Consistent with this hypothesis, the increased expressing tumors on HER2. A number of studies using migratory activity induced by the experimental over- antisense, ribozyme or small interfering RNA (siRNA) expression of HER2 can be suppressed by anti-CXCR4 methodologies to suppress HER2 expression in human antibodies (Li et al., 2004). cancer cell lines consistently show that HER2-overexpressing tumor cells are dependent on HER2 and Induction of ETS undergo growthinhibition and apoptosis in cell culture, ETS (E26 transformation specific) transcription factors or tumor regression in vivo, in the absence of HER2 are almost universally overexpressed in HER2-amplified expression, while tumor types that do not overexpress breast cancers and they are also overexpressed and are HER2 are not sensitive to HER2 knockdown (Colomer essential in MMTV-neu-induced mammary tumorigen- et al., 1994; Juhl et al., 1997; Roh et al., 2000; esis (Shepherd et al., 2001; Neve et al., 2002). HER2 Choudhury et al., 2004; Faltus et al., 2004). A kinase- overexpression specifically leads to the bimodal activa- dead mutant of activated HER2 competes withand tion of the ETS transcription factor ER81 (Goel and reverses the transformed phenotype induced by acti- Janknecht, 2003), which mediates the induction of vated HER2 (Messerle et al., 1994). Intracellularly expression of the catalytic subunit of telomerase (Goueli expressed single-chain antibodies that target and in- and Janknecht, 2004). activate HER2 revert HER2-induced transformation or induce apoptotic cell deathin HER2-overexpressing Other downstream or cooperating pathways tumor cells (Beerli et al., 1994; Deshane et al., 1996). HER2 overexpression leads to increased expression of hypoxia-inducible factor 1a (HIF-1a) through Akt HER2 withdrawal models leading to increased expression of vascular endothelial Tetracycline inducible systems offer even more elegant growthfactor (VEGF) and increased surface expression models for analysis of oncogene addiction. NIH3T3 of fibronectin receptors (Laughner et al., 2001; Li et al., cells transformed by tetracycline-regulated overexpres- 2005; Spangenberg et al., 2006). VEGF expression is also sion of HER2 revert from the transformed phenotype induced by HER2 overexpression through a HIF-1a- and their mouse implanted tumors regress when HER2 independent mechanism (Loureiro et al., 2005). expression is withdrawn (Baasner et al., 1996; Schiffer Numerous other pathways have been implicated in et al., 2003). Tetracycline-induced expression of acti- HER2-mediated transformation, although they are vated HER2 in squamous epithelia of mice results in muchless well characterized. HER2-overexpressing severe hyperplastic abnormalities of squamous epithelial breast cancers are characterized by increased expression tissues, which reverse upon withdrawal of the HER2 of MMP-2 (matrix metalloproteinase-2) and MMP-9 transgene expression (Xie et al., 1999). Tumors in (matrix metalloproteinase-9) (Pellikainen et al., 2004). MMTV-neuT mice are also dependent on continued HER2 overactivity also promotes the activation of the oncogene expression. In the MMTV-rtTA/TetO-NeuNT nuclear factor-kB antiapoptotic pathway (Makino et al., bitransgenic variant of this model regulated by doxycy- 2004). Involvement of myc downstream of HER2 has cline, when expression of the neuT oncogene is induced been proposed, although it remains to be defined and in the mammary tissue of adult mice, the formation of may be complex (Hynes and Lane, 2001). multiple mammary tumors and lung metastases is induced, and the entire primary tumor and metastatic disease fully regresses when neuT expression is with- Tumor dependence on HER2 drawn (Moody et al., 2002). Eachof thesemodels is subject to specific criticisms. While the tumorigenic potential of HER2 overexpres- For example, the antisense or siRNA approaches have sion has been clearly demonstrated in numerous model nonspecific effects, the NIH3T3 fibroblast models are

Oncogene The oncogene HER2 in human cancer pathogenesis MM Moasser 6480 not representative of what is principally an epithelial Numerous well-supported experimental models implicate oncogene in humans, and the transgenic models may be diverse mechanisms involved in HER2-mediated tumor- too simplistic and understate the genetic complexity of igenesis and a unified mechanistic model cannot currently the human disease. But taken in aggregate, the existing be proposed. It is possible that the position of HER2 in the data from all the different models and approaches signaling web places it in control of numerous pathways are highly consistent and collectively make a highly that can contribute to malignant progression such that the compelling case that HER2-induced tumors are addic- amplification of HER2 as a single event can substitute for ted to HER2. This has made HER2 one of the most several events in the multistep model of carcinogenesis. sought after targets in cancer drug development. Indeed, HER2-amplified breast cancers occur at an earlier age than other types of breast cancers consistent with a fast-track route to oncogenesis in these cancers (Swede Conclusion et al., 2001; Crowe et al., 2006). The highly oncogene- addicted nature of these cancers also attests to a HER2 Numerous experimental models now solidly support the function that is not easily supplanted, possibly owing to its hypothesis that HER2 overexpression promotes tumor- multiple oncogenic roles. The critical driving role of HER2 igenesis and the finding of HER2 amplification and in human cancers, and the large number of patients overexpression in many human breast cancers and its link affected by this type of cancer has made HER2 an with the biology of this disease now clearly implicate this ideal target for the development of rationally designed oncogene in the pathogenesis of this type of human cancer. anticancer drugs.

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