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Abstract

  1. Top of page
  2. Abstract
  3. HER receptors family and its ligands
  4. NETWORK FUNCTION IN DEVELOPMENT AND DIFFERENTIATION
  5. HER-2: PROLIFERATION OR DIFFERENTIATION?
  6. CONCLUDING REMARKS
  7. LITERATURE CITED

Members of the epidermal growth factor receptor family of receptor tyrosine kinases play a critical role in both development and oncogenesis. The latter is suggested by the frequent overexpression of HER-2, EGFR, and HER-3 in some human carcinomas, primarily breast and squamous cancer. The biological activities of the EGFR family are exerted through various ligand–receptor and receptor–receptor interactions. One receptor that plays a central role in this signaling network is HER-2/Neu, which is considered the preferred heterodimerization partner for other members of the EGFR family. The role of these receptors and their ligands in development is discussed, with particular emphasis on their ability to mediate a variety of pathways and cellular responses, including proliferation, differentiation, and apoptosis. © 2004 Wiley-Liss, Inc.


HER receptors family and its ligands

  1. Top of page
  2. Abstract
  3. HER receptors family and its ligands
  4. NETWORK FUNCTION IN DEVELOPMENT AND DIFFERENTIATION
  5. HER-2: PROLIFERATION OR DIFFERENTIATION?
  6. CONCLUDING REMARKS
  7. LITERATURE CITED

The flow of information from the extracellular environment into the cell is at the core of a functional biological system. Receptor tyrosine kinases (RTKs) are primary mediators of many of these signals and thus determine whether the cell grows, differentiates, migrates, or dies. RTKs are cell surface allosteric enzymes consisting of a single transmembrane domain that separates an intracellular kinase domain from an extracellular ligand-binding domain. Ligand binding induces receptor homo- or heterodimerization which is essential for activation of the tyrosine kinase and subsequent recruitment of target proteins, in turns initiating a complex signaling cascade that leads into distinct transcriptional programs. These involve not only the proto-oncogenes fos, jun, and myc, but also a family of zinc-finger-containing transcription factors that include Sp1 and Egr1, as well as Ets family members such as GA-binding protein (GABP) (Schaeffer et al., 1998). The HER family of RTKs consists of four receptors: epidermal growth factor receptor (EGFR, also called HER-1 or erbB-1), HER-2 (also called erbB-2 or Neu), HER-3 and HER-4 (also called erbB-3 and erbB-4, respectively).

Extensive receptor–receptor interactions and the existence of a wide group of ligands underlies the enormous potential for diversification of biological messages mediated by the HER family. These peptide ligands are produced as transmembrane precursors, and the ectodomains are processed by proteolysis, which leads to shedding of soluble growth factors (Massagué and Pandiella, 1993). There are several HER-specific ligands, all sharing an EGF-like motif of 45–55 amino acids and including six cysteine residues that interact covalently to form three loops. This region is probably the most important, conferring binding specificity by which HER ligands can be divided into three groups. The first group includes EGF, amphiregulin (AR), and transforming growth factor-α (TGF-α), which bind specifically to HER-1. The second group includes betacellulin (BTC), heparin-binding EGF (HB-EGF), and epiregulin (EPR) (Yarden, 2001), which exhibit dual specificity for HER-1 and HER-4. The third group is composed of the neuregulins (NRG, also called Neu differentiation factors, NDFs, or heregulins, HRG) and includes two subgroups based on their capacity to bind HER-3 and HER-4 (NRG-1 and NRG-2) or only HER-4 (NRG-3 and NRG-4) (Zhang et al., 1997; Harari et al., 1999). NRGs, are expressed predominantly in parenchymal organs and in the embryonic central and peripheral nervous systems. The different NRG isoforms are the products of alternative splicing of a single gene (Marchionni et al., 1993).

Each of the many ligands has a different preference for stabilizing distinct receptor dimers, and each receptor dimer has a different set of tyrosine autophosphorylation sites, which serve as docking sites for specific SH2-containing proteins and recruit different combinations of signaling molecules (Di Fiore et al., 1990; Olayioye et al., 2000; Yarden, 2001). Further complexity of this system derives from the existence of a receptor that is activated only by heterodimerization with another ligand-bound member of the family: HER-2, which enhances and stabilizes dimerization, but apparently has no direct or specific ligand (Horan et al., 1995), and HER-3 (Kim et al., 1998), a receptor that can recruit novel SH2-containing proteins, but that is devoid of kinase activity itself due to substitutions of critical residues in its kinase domain (Guy et al., 1994). At least nine different homo- and heterodimers of HER proteins exist, but their formation displays a distinct hierarchy. In this network, HER-2 plays a major coordinating role, since each receptor with a specific ligand appears to prefer HER-2 as its heterodimeric partner (Tzahar et al., 1996; Graus-Porta et al., 1997). This preference is further biased upon overexpression of HER-2, as seen in many types of human cancer cells. HER-2-containing heterodimers are characterized by extremely high signaling potency because HER-2 dramatically reduces the rate of ligand dissociation, allowing strong and prolonged activation of downstream signaling pathways (Beerli et al., 1995; Graus-Porta et al., 1995). The most important intracellular pathways activated by HER receptors are those involving mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI-3K) (Olayioye et al., 2000; Yarden and Sliwkowski, 2001). HER-3, which contains six docking sites for the p85 adaptator subunit of PI-3K, efficiently couples to this pathway (Fedi et al., 1994; Prigent and Gullick, 1994). Based on observations that a major consequence of targeting overexpressed HER-2 in breast cancer cell lines is decreased PI-3K activity (Lane et al., 2000; Neve et al., 2000; Basso et al., 2002), and that constitutive tyrosine phosphorylation of HER-3 depends on the activity of overexpressed HER-2 (Alimandi et al., 1995). Holbro et al. (2003) have suggested that HER-2/HER-3 dimers are the oncogene-driven unit. On the other hand, complete inhibition of breast carcinoma proliferation by a HER-1-specific tyrosine kinase inhibitor suggests a central role for HER-1 (Campiglio et al., 2004).

NETWORK FUNCTION IN DEVELOPMENT AND DIFFERENTIATION

  1. Top of page
  2. Abstract
  3. HER receptors family and its ligands
  4. NETWORK FUNCTION IN DEVELOPMENT AND DIFFERENTIATION
  5. HER-2: PROLIFERATION OR DIFFERENTIATION?
  6. CONCLUDING REMARKS
  7. LITERATURE CITED

Expression patterns of HER receptors and their ligands, as well as targeted inactivation of components of the HER signaling network have highlighted the importance of short-range ligand–receptor interactions, especially in mid-gestation processes. Apparently, the network is involved primarily in two types of interactions: (1) mesenchyme–epithelia crosstalk and (2) neuronal effects on target cells, including muscle, astroglia, oligodendrocytes, and Schwann cells. NRG, for example, is synthesized by mesenchymal or neuronal cells and influences adjacent epithelial or non-neuronal cells, respectively, with respect to their differentiation, proliferation, and migration. This may explain the crucial role of the HER receptor family in development of the cardiovascular system, nervous system, mammary gland ,and probably others (Table 1).

Table 1. Summary of the effect of HER receptors knockout and conditional mutant animals
 HER-1−/−HER-2−/−HER-3−/−HER-4−/−HER-2 conditional mutantsHER-4 conditional mutants
  • *

    Causes of embryonic lethality.

SurvivalEmbryonic or perinatal lethalityEmbryonic day-10 lethalityEmbryonic day-13.5 lethalityEmbryonic day-10 lethality  
Cardiovascular system Aberrant cardiac development*Defective cardiac valve formation*Aberrant cardiac development*Severe dilated cardiomyopathyAberrant cardiac development
Nervous system Aberrant peripheral development*Aberrant peripheral development*Aberrant peripheral development*Aberrant developmentAberrant development
Mammary glandImpaired development   Defect in development late in gestation and early post-partumUnpaired lactation
EpitheliumEpithelial defects as wavy hair     

Cardiovascular system

An essential role for the HER receptor family in mid-gestation development was indicated by embryonic lethality of HER-2- (Lee et al., 1995), HER-4- (Gassmann et al., 1995), and NRG-deficient mice at around day-10 post-fertilization due to aberrant cardiac and peripheral nervous system development. The trabeculae, finger-like extensions of the ventricular myocardium, fail to develop in these mice and the resulting mutant heart is characterized by irregular beat, an enlarged common ventricle, and reduced blood flow. HER-3-knockout mice have less severe heart defects and consequently survive several days longer (to around embryonic day-13.5), displaying normal heart trabeculation but defective valve formation. The role of HER-4 has been further established in HER-4-knockout mice by re-expressing HER-4 under the regulatory control of the cardiac α-myosin heavy chain (αMHC) promoter (Morris et al., 1999; Tidcombe et al., 2003). Cardiac-rescued MHC-HER4 HER4−/− mice are viable, but display abnormalities in the central nervous system and mammary gland. The mid-gestation cardiac defect in HER-2 knockout animals has been circumvented through the use of Cre-Lox technology, a conditional mutagenesis approach based on the Cre DNA recombinase-mediated deletion of a DNA segment flanked on both sides by two loxP sequences. When the recombinase is expressed under an appropriate promoter, this method allows the introduction of a mutation in an inducible and tissue-specific manner. Conditional mutagenesis of the HER-2 gene in murine ventricular cardiomyocytes (Ozcelik et al., 2002) revealed development of severe dilated cardiomyopathy, with signs of cardiac dysfunction generally appearing by the second postnatal month. Based on these findings, the authors concluded that signaling from the HER-2 receptor, which is enriched in T-tubules in cardiomyocytes, is crucial for adult heart function. In light of the adverse cardiac side effects observed in breast cancer patients treated with the monoclonal anti-HER-2 antibody Trastuzumab (Slamon et al., 2001), an improved understanding of the molecular mechanisms by which HER-2 regulates heart function is especially important.

Nervous system

The NRGs exert many functions in neural development. Roles for NRG-1-HER signaling in neural development have been demonstrated in mice carrying an HER-3 null mutation (Riethmacher et al., 1997), as well as by selective mutations of NRG-1 ectodomains (Meyer et al., 1997; Wolpowitz et al., 2000), by MHC-HER-specific expression (Morris et al., 1999; Tidcombe et al., 2003), and by Cre-targeted HER-2 ablation in Schwann cells (Garratt et al., 2000). In all of these mice, peripheral motorneuron axons defasciculate as they enter the muscle mass and fail to form mature neuromuscular junctions. Aberrant cranial nerve architecture and increased numbers of large interneurons within the cerebellum have been demonstrated in MHC-HER4 HER4−/− mice, while loss of NRG-1-HER signaling led to hypoplasia of the sympathetic ganglion chain and the neural crest-derived portion of the cranial sensory ganglia (Kramer et al., 1996; Erickson et al., 1997; Riethmacher et al., 1997; Britsch et al., 1998). Moreover, the NRG-1-HER mutants were completely devoid of Schwann cells in peripheral nerves at late development stages (Woldeyesus et al., 1999; Wolpowitz et al., 2000). Thus, NRG-1 signaling through the HER-2/HER-3 heterodimer is required for normal Schwann cell development. The role of HER-2 signaling in later development of the Schwann cell lineage was also analyzed using conditional mutagenesis (Garratt et al., 2000). In that study, the Cre allele introduced the HER-2 mutation in maturing myelinating Schwann cells, allowing the initial development of Schwann cell precursors to proceed unperturbed. These conditional HER-2 mutants displayed peripheral nerve hypomyelination associated with neuropathy, a phenotype reminiscent of the pathology in patients with Charcot-Marie-Tooth disease (Benstead and Grant, 2001). Thus HER-2 is the first signaling molecule for which a role in control of Schwann cell myelination has been demonstrated in vivo. Moreover, Kim et al. (2003) have very recently demonstrated that HER-2 signaling is also critical for oligodendrocyte differentiation in vivo, to date, no data have been reported on nervous system toxicity in patients treated with anti-HER-2-targeted therapy. Nevertheless, patients long-term treated should be carefully monitored for potential side effect since a possible role for HER-2 in mature nervous system tissue cannot be excluded.

Epithelial development

In contrast to the embryonic lethality caused by HER-2 inactivation, mice carrying a naturally occurring germ-line mutation in the kinase domain of EGFR known as Waved-2 (hypomorphic allele with severely reduced catalytic activity) are completely viable and display only epithelial defects, such as a wavy hair phenotype. Mutant mice display impaired epithelial development in several organs, resulting in phenotypes ranging from peri-implantation death to live progeny with abnormalities in multiple organs, such as liver and skin depending on the genetic background. (Luetteke et al., 1994; Fowler et al., 1995).

Mammary gland

The importance of HER receptor family and ligands in human mammary carcinoma has evoked keen interest in the normal functions of these receptors in the mammary gland, an organ that undergoes considerable postnatal development. Analyses of HER family ligands in mammary development have revealed a complicated picture. RNAs encoding the majority of the HER-specific growth factors such as AR, BTC, HB-EGF, EPR, EGF, NRG1, and TGFα are all present, each with a unique temporal pattern of transcriptional regulation during the normal course of mammary development, maturation, and involution (Schroeder and Lee, 1998).

HERs play several normal non-oncogenic roles in regulating growth, differentiation, apoptosis, and/or remodeling in normal mammary glands. These receptors are differentially expressed in mammary epithelial and/or stromal cells during various stages of development (Table 2). In the mouse virgin gland, HER-1 and HER-2 colocalize in all major cell types during ductal morphogenesis, but localized differentially in the mature gland. EGFR and HER-2 are preferentially expressed in lactating ducts and alveoli, and HER-3 and HER-4 are more pronounced in alveoli (Schroeder and Lee, 1998). Interestingly, a switch from HER-3 to HER-4 expression was observed in the developing mammary gland, suggesting that the two receptors play different roles in mammary morphogenesis. Activated EGFR and HER-2 are highly expressed in extracts of mammary glands collected at puberty, suggesting a prominent role of these receptors at this stage of development, while both are expressed to only a minor extent in mammary glands in late-stage pregnancy and in lactation (Sebastian et al., 1998). By contrast, HER-3 and HER-4 are active in mammary glands mostly during pregnancy and lactation (Yang et al., 1995). With respect to the signaling pathways activated by HER-2, Niemann et al. (1998) demonstrated that formation of branched tubules relies on a pathway involving PI-3K, whereas alveolar morphogenesis requires MAPK.

Table 2. Expression of HER receptors during the different stages of mammary gland development
 HER-1HER-2HER-3HER-4
PubertyPresent at high levelsPresent at high levelsAbsent or present at low levelsAbsent or present at low levels
PregnancyPresentPresentPresent at high levelsPresent at high levels
LactationPresentPresentPresent at high levelsPresent at high levels
InvolutionPresentPresentPresentAbsent

Analysis of the role of HER receptors in development of immature mammary gland have been hampered by mid-gestation lethality due to disruption of HER-2 (Lee et al., 1995), HER-3 (Riethmacher et al., 1997), and early postnatal lethality (within 3 days of birth) in HER-1−/− mice, all prior to the major transitions of mammary development (Miettinen et al., 1995). However, the prolonged survival of a fraction of HER-1−/− mice enabled the determination that postnatal ductal development was seriously impaired. These mice are characterized by a reduced proliferation of mammary epithelium and stroma, as well as a substantial loss of periductal fibroblasts. Although cardiac-rescued MHC-HER4 HER4−/− mice reach adulthood and are fertile, they show abnormal mammary lobulo-alveolar differentiation and defective lactation (Tidcombe et al., 2003).

Mammary functions of EGFR, HER-2, and HER-4 have also been assessed using cytoplasmic, truncated dominant-negative forms of the receptors, under the control of the mouse mammary tumor virus (MMTV) promoter. Transgenic animals expressing dominant-negative MMTV-driven truncated HER-2 have significant defects in mammary development late in gestation and early postpartum, with failure of alveolar expansion (Jones and Stern, 1999). Ductal development occurs in these animals, but they have lactation problems, and mammary glands early postpartum show an immature phenotype more typical of late pregnancy (Tidcombe et al., 2003). The MMTV-driven truncated HER-4 dominant-negative phenotype resembles that in mice with inactivated mammary differentiation factors Stat5s in the mammary gland (Liu et al., 1997; Teglund et al., 1998; Jones et al., 1999). Targeted recombination-mediated inactivation of HER-4, through Cre-Lox technology, has demonstrated that this receptor is an essential mediator of STAT5 signaling (Long et al., 2003). Mice with Cre-Lox deletions of both HER-4 alleles in the developing mammary gland fail to accumulate lobulo-alveoli or successfully engage lactation at parturition due, in part, to impaired epithelial proliferation. These data do not reveal any indispensable role for a particular member of the family in mammary gland development. Moreover, the cross-talk between HERs and steroid hormone receptors in mammary gland development remains to be established. It seems very likely that these two receptor types act synergistically and that inhibition of both pathways is required for complete ablation of mammary gland development. In that context, Tamoxifen, an antagonist of estrogen, shown to prevent 50% of breast carcinoma development (Radmacher and Simon, 2000), might be used in combination with anti-HER therapy to completely inhibit mammary gland development.

HER-2: PROLIFERATION OR DIFFERENTIATION?

  1. Top of page
  2. Abstract
  3. HER receptors family and its ligands
  4. NETWORK FUNCTION IN DEVELOPMENT AND DIFFERENTIATION
  5. HER-2: PROLIFERATION OR DIFFERENTIATION?
  6. CONCLUDING REMARKS
  7. LITERATURE CITED

HER-2 overexpression, occurring in 25–30% of human breast cancers, is associated to shorter time to relapse and lower overall survival (Slamon et al., 1987; Ménard et al., 1996, 1999, 2002). HER-2 oncogenic action is exerted through activation of the PI-3K pathway, which inhibits apoptosis (Sepp-Lorenzino et al., 1996; Kulik et al., 1997; Nelson and Fry, 2001). The survival signal is also normally coupled to the activation of the mitogenic signal involving MAPK pathway recruitment. Increased HER-2 expression in cancer enhances and prolongs signaling from both the PI-3K and MAPK pathways (Karunagaran et al., 1996; Olayioye et al., 2001; Neve et al., 2002), associating upregulation of this receptor to the malignant phenotype. Nevertheless, HER-2 transfection of some cell lines leads to decreased plating and cloning efficiency, decreased growth rate (Giani et al., 1998; Casalini et al., 2001), inhibition of entry into the S-phase of the cell cycle, and differentiation (Giani et al., 1998). This is consistent with the induction of differentiation (Peles et al., 1992), growth inhibition (Daly et al., 1997) and/or apoptosis induced by heregulin and some antibodies against HER receptors (Aguilar et al., 1999; Guerra-Vladusic et al., 1999, 2001; Le et al., 2001).

An important role for HER receptors in apoptosis has been recently demonstrated. Indeed, UVB-induced apoptosis of human keratinocytes occurs through HER-1 and HER-2 activation since a specific inhibitor of the receptors, DAPH, or neutralizing antibodies to either HER-1 or HER-2, protect cells from UVB-induced apoptosis (Lewis et al., 2003). Moreover, several experimental lines of evidence demonstrate that, under certain conditions, the activation of these receptors leads directly to the apoptotic death of the cell. For example experimentally induced increases in HER-1 expression levels, predictably lead to apoptosis in a variety of cell types (Hognason et al., 2001; Lehto, 2001). HER-2 receptor activation has been found to up-modulate p53 expression (Bacus et al., 1996), a major determinant of growth, differentiation, and induction of apoptosis i.e., wild-type p53 leads to apoptosis/differentiation, whereas mutated p53 leads to proliferation (Fig. 1) (Giani et al., 1998; Casalini et al., 2001). It has also been demonstrated that HRG stimulation of HER-2-overexpressing cells leads to enhanced c-Myc protein synthesis through activation of the PI3K/Akt/mTOR pathway (Galmozzi et al., 2004), which in turn could act as transcriptional factor for p53 leading to its upregulation (Fig. 2).

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Figure 1. A: Colony formation of HER-2-transfected cells bearing wt or mutated p53. Cells were transfected with HER2 c-DNA or with empty vector (control). After 3 weeks of selection, colonies were counted. Results are given as mean percentage (bars, SE of two separate experiments) of colony inhibition in comparison to control cells. B: Apoptosis in HER2-transfected cells. Cells bearing wt or mutated p53 were seeded in chamber slides and transiently transfected with HER2 c-DNA cloned in a vector expressing a fusion product with the N terminus of green fluorescent protein. Control is represented by cells transfected with empty vector expressing only green florescence protein. Apoptosis is expressed as mean percentage of apoptotic nuclei in green transfected cells in comparison to control cells.

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thumbnail image

Figure 2. Schematic diagrammatic representation of the possible signal transduction cascades that are involved in HER receptors activation.[Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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The finding that HER-2 overexpression is associated with proliferation in cell lines with mutated p53 is consistent with the frequent overexpression of HER-2 in breast tumors with p53 alterations (James and Olson, 1989). However, the existence of HER-2-overexpressing, p53 wild-type tumors suggests the presence of other alterations related to the apoptotic pathway in tumor cells that allow the shift from apoptosis to proliferation related to HER-2 oversignaling (Casalini et al., 2001; Huang et al., 2002).

CONCLUDING REMARKS

  1. Top of page
  2. Abstract
  3. HER receptors family and its ligands
  4. NETWORK FUNCTION IN DEVELOPMENT AND DIFFERENTIATION
  5. HER-2: PROLIFERATION OR DIFFERENTIATION?
  6. CONCLUDING REMARKS
  7. LITERATURE CITED

The HER family of receptor tyrosine kinases plays a crucial role in the development of the nervous system, cardiovascular system, and the mammary gland, mediating activities that are various and often opposite: proliferation, differentiation, and apoptosis. The ability to promote different cellular responses appears to seat in a complex protein network which acts through and activates several pathways, and might underlie the multifaceted role of this receptor family in physiological cellular regulation and in carcinogenesis. The HER network is actually a powerful mechanism controlling cell fate through subtle regulation; indeed, deregulation of this network is a common finding in human cancers.

To date, it remains unclear whether HER receptor activity is crucial in driven transformation processes or whether their action is directed mainly to conferring a proliferative advantage in tumor progression. If overexpression of a particular HER member were shown to be essential for tumor existence, HER-targeted therapies would be expected to reverse transformation. However, the use of receptor tyrosine kinase inhibitors, for example, ZD1836, did not lead to improved clinical outcome of patients, in recent clinical phase III trial (Manegold, 2003). The key role of HERs in tumor development is likely exerted during the early stage of the transformation process, with their overexpression providing a proliferative advantage that allows tumor cell survival during clonal selection. This concept is supported by higher frequency of HER2 overexpression in DCIS than in more advanced breast carcinoma (Latta et al., 2002). Thus, it appears that HER-2 overexpression alone is insufficient for the maintenance and progression of the tumor, which selects further alterations for its establishment.

Further investigations of HER multiple functions are needed to improve our understanding of their physiological role in the development and function of several organs and their role in oncogenesis. Such understanding will provide the rationale basis for safe and effective HER-targeted therapies.

LITERATURE CITED

  1. Top of page
  2. Abstract
  3. HER receptors family and its ligands
  4. NETWORK FUNCTION IN DEVELOPMENT AND DIFFERENTIATION
  5. HER-2: PROLIFERATION OR DIFFERENTIATION?
  6. CONCLUDING REMARKS
  7. LITERATURE CITED
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