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Tyrosine kinase signalling in breast cancer: ErbB family receptor tyrosine kinases

Abstract

ERBB family receptor tyrosine kinases are overexpressed in a significant subset of breast cancers. One of these receptors, HER2/neu, or ErbB-2, is the target for a new rational therapeutic antibody, Herceptin. Other inhibitors that target this receptor, and another family member, the epidermal growth factor (EGF) receptor, are moving into clinical trials. Both of these receptors are sometimes overexpressed in breast cancer, and still subject to regulation by hormones and other physiological regulators. Optimal use of therapeutics targeting these receptors will require consideration of the several modes of regulation of these receptors and their interactions with steroid receptors.

Introduction

The close of the millenium is marked by unprecedented advances in our understanding of the mechanisms that underlie carcinogenesis. Each procarcinogenic pathway presents pharmacologists with an array of therapeutic targets. Most importantly, the first rational therapeutic agents targeted at oncogene products have now navigated the tortuous drug development pipeline. A monoclonal antibody, 'Herceptin', which binds to the receptor tyrosine kinase (RTK) Her-2/Neu/ErbB-2 is effecive for treatment of a subset of patients with advanced breast cancer [1**, 2**]. This antibody is at the vanguard of a host of therapeutic compounds that are under development to antagonize the acivities of ErbB family receptors.

The development and application of clinical tools that intervene in ErbB-regulated processes will be most effective if close attention is paid to the biologic properties of these RTKs. Signaling through these receptors, even when they are overexpressed in tumors, is still subject to regulation. This means that there are potentially many points of vulnerability at which therapeutic interventions can be targeted. Furthermore, the ability of overexpressed ErbB family RTKs to alter responses to genotoxic drugs and to steroid hormones means that ErbB-targeted therapies will have complex interactions with existing breast cancer therapeutic agents.

Amplification of ErbB family receptors

The ERBB family consists of four closely related genes: ERBB (HER), ERBB-2 (HER-2, NEU), ERBB-3 (HER-3), and ERBB-4 (HER-4). ERBB (HER) encodes the prototype EGF receptor, and the other genes encode structurally similar RTKs. ERBB-2 is amplified (extensively reduplicated) in 15-30% of breast cancers [3**]. Amplification is more common in tumors from patients with lymph node metastases than in those from node-negative patients (for review [4*]). Amplification and/or overexpression of ErbB-2 occurs most often (up to 60%) in in situ carcinomas [4*,5], so ErbB-2 overexpression may be an early change. ErbB-2 overexpression in conjunction with amplification, and in another few percent of breast cancers without gene amplification, is further accentuated by transcriptional upregulation of ERBB2, which is mediated by the transcription factor AP-2 [6].

The finding that a particular tumor type is associated with amplification of a particular gene suggests that the amplification incurs a selective advantage for the tumor. Amplicons may affect more than one gene, but ERBB2 is a commone element in 17q21 amplification. Overexpression of coamplified genes, including GRB7, may also contribute to selection for this genetic change [7,8].

EGF family receptors normally function in regulation of mammary growth and differentiation. Overexpression of ErbB-2 in tissue culture or in transgenic mouse mammary glands leads to transformation, tumorigenicity, and metastasis, which is unusual for RTKs that are overexpressed in the absence of ligands [9*,10]. These findings implicate ErbB-2 as a major player in initiation and/or progression of breast cancer. This conclusion has now been substantiated with the demonstrated efficacy of ErbB-2-targeted therapeutic antibodies.

Other ErbB family receptors apart from ErbB-2 are amplified or overexpressed in breast cancer. Amplification and overexpression of the EGF receptor is well documented, but there is a wide range in the reported frequencies of EGF receptor overexpression [3**,11*]. Overexpression of ERBB3 has been reported in breast cancer [12,13**,14]. Thus, EGF receptor, ErbB-2, and ErbB-3 are positively regulated in breast cancer. In contrast, overexpression of ErbB-4 is uncommon in breast cancer, and ErbB4 expression may be suppressed in carcinoma [15,16]. This might indicate that ErbB4 is either unimportant, or actually antagonizes carcinogenesis. In fact, there is evidence that ErbB4 expression is associated with positive prognostic indicators in breast cancer [17,18].

Regulation of ErbB family receptors by peptide growth factors

EGF family receptors are directly regulated by binding of diverse polypeptide hormones that each contain a 6-kDa domain that is homologous to EGF (for review [19*,20*,21*]). The ligands consist of amphiregulin, betacellulin, EGF, epiregulin, heparin-binding EGF-like growth factor, various forms of neuregulin (neuregulin-1, -2, -3, and -4), and transforming growth factor (TGF)-α. They have different abilities to bind to and activate the ErbB family receptors when expressed singly. For example, EGF binds to the EGF receptor, but not to ErbB2, ErbB3, or ErbB4, and neuregulin-1 binds to ErbB3 or ErbB4, but not to the EGF receptor [19*,20*]. EGF family receptors can also be activated indirectly by agonists that bind serpentine G protein-coupled receptors [22].

Ligand-dependent regulation of the ErbB family of receptors is expanded through the promiscuous formation of receptor heterodimers [19*,20*,23]. In cells that express EGF receptor and ErbB2, any of the EGF agonists will induce formation of EGF receptor-ErbB2 heterodimers, as well as EGF receptor-EGF receptor homodimers. This cross-activation extends to most of the receptor combinations, so that activation of one receptor will generally lead to some activation of other coexpressed ErbB family RTKs. Heteromerization can also enhance the affinity of ligand binding [24*,25]. Heteromerization with other ErbB family receptors is required for activation of ErbB-3, which is devoid of intrinsic catalytic activity [26].

ErbB-2 is an orphan receptor, because none of the soluble ligands bind to ErbB-2 that is expressed independently. ErbB-2 is strongly activated through interactions with other EGF family receptors [27**], however, and ligand-induced ErbB-2 heteromers are favored over other heteromers or homomers [28]. Because ErbB-2 is jointly expressed with other ErbB family receptors, it can be thought of as a common subunit that expands the signaling repertoire of the other ErbB family receptors [20*].

Differential regulation of the receptors is important because each receptor has unique signaling properties [19*,20*,29]. ErbB-3 is an extreme case, because it has multiple phosphoinositide 3-kinase-binding sites, and couples strongly to this signaling molecule [30]. The response of cells depends on which of the receptors are activated. Depending on the specific cell context, activation of these receptors may promote proliferation, motility, differentiation, or even apoptosis [31,32,33]. On aggregate, these interactions may significantly add to, or even alter the response of cells to ligands [19*]. For example, ErbB2 greatly augments the amplitude and duration of mitogenactivated protein kinase activation by EGF or neuregulin [34**]. The differential activation of different receptors and receptor combinations, as well as the different signaling abilities of the ErbB receptors, contributes to the extraordinary diversity of signals that can be regulated by the ligands. It also means that the response to a particular agonist is affected by the spectrum of agonistic hormones that regulate the system, because there may be interreceptor competition for dimerization partners.

Activation of ErbB receptors induces dimerization and tyrosine phosphorylation. The activation-induced phosphopeptides recruit docking proteins that themselves convey the signal further. Although specific ErbB receptors have been traced to specific responses, less is known about how these responses correlate with recruitment of specific pathways and substrates. Once activated, signals are damped through ligand-receptor dissociation [25], throught phosphorylation (eg by protein kinase C), and by receptor-mediated endocytosis, which can be followed by recycling to the cell surface, or proteolytic destruction of the receptor. The activities of tyrosine phosphatases, including basal phosphatases and those that are recruited after ligand activation, will further influence the intensity and duration of signaling.

ErbB family receptors in mammary gland development

The frequent association of ErbB receptor signaling with breast cancer reflects the fact that the four ErbB receptors are involved in normal mammary gland development. The female mammary gland undergoes extensive postnatal development under the influence of systemic hormones. Peptide hormones including EGF family ligands, fibroblast growth factors [35], and insulin-like growth factor-I are thought to act under control of the systemic hormones as local mediators of mammary development. All four ErbB family receptors are expressed in the mammary gland of adult females, but EGF receptor and ErbB-2 are preferentially expressed in young females [36,37**,38**].

The first postnatal episode of mammary development occurs at puberty, and leads to elongation and branching of the mammary ducts to extend throughout the fatty mesenchyme. EGF receptor and ErbB-2 are present in stroma and epithelium, and are tyrosine-phosphorylated, which is indicative of signaling activity [37**,38**]. The mid-gestation lethality of disruptions in ErbB-2, ErbB-3, and ErbB-4 has hampered characterization of mammary functions of these receptors [39*,40*,41*]. The EGF receptor is important at puberty, because expression of a dominant-negative EGF receptor impairs ductal morphogenesis [42**]. Surprisingly, reconstitution of stromal/epithelial tissue chimeras showed that EGF receptor is absolutely required in mesenchyme, but not in the epithelium [43**]. This does not rule out redundant functions for EGF receptor in the epithelium.

The second wave of activation (tyrosine phosphorylation) of ErbB family receptors occurs in pregnancy [37**,38**]. The activation occurs later than the major period of proliferation. Instead, ligand expression and receptor activation is most extensive late in pregnancy and after parturition. Dominant-negative ErbB-2 and ErbB-4 transgenes interfere with lobuloalveolar expansion and milk protein production early and late postpartum, respectively, which is consistent with the ability of neuregulin-activated ErbB-2 to drive mammary differentiation [36, 44*,45**,46*].

At least five EGF family ligands are expressed at various phases of mammary development, where they may promote proliferation and/or differentiation [37**,38**]. Disruption of mouse amphiregulin, EGF, and TGF-α genes identified amphiregulin as a particularly important ligand for regulation of both ductal outgrowth and lactation. This is consistent with the high expression of amphiregulin in the mammary gland [47]. In both the amphiregulin knockout mice, and transgenic mice that express the ErbB-4 dominant-negative transgene, the lactational phenotype is associated with a failure to activate the important intracellular mediator of mammary development Stat5, an SH2 domain-containing transcription factor that regulates production of milk proteins [45**,48**].

The functions of ErbB receptors in the mammary gland may be connected with their roles in carcinogenesis. EGF agonists are mitogenic in the mammary fat pad of young females [49], and probably work by concomitant activation of EGF receptor and ErbB-2. The initial selection for overexpression of these receptors in cancer precursor cells might be based on mitogenic coupling of the receptors in ductal epithelial cells. The elongation of mammary ducts, which is impaired in amphiregulin-disrupted mice [48**], involves processes that mirror aspects of tumor invasion, including changes in intercellular adhesion, and motility. These changes, even divorced from mitogenic activity of the receptors, may be important in early stages of tumor progression. Interestingly, the proliferation and survival of cells in the mammary gland seems unaffected by disruption of amphiregulin. Similarly, defects in terminal differentiation and lactation of transgenic mice that express dominant-negative ErbB-2 and ErbB-4 occur after the major period of proliferation [44*,45**].

ErbB receptor activation and signaling heterogeneity

Activation of oncogenes such as RAS in human cancer is caused by structural mutations that strongly and constitutively activate Ras signaling. The tumor-associated changes in ErbB family receptors in breast cancer are generally changes in expression, however, so that normal modes of regulation are still in operation. Two tumors that overexpress an ErbB family receptor to the same degree may be influenced by the receptor in quantitatively or qualitatively different ways if other regulatory influences differ.

The fact that overexpressed EerbB receptors can still be regulated may facilitate drug development. Negative regulators of these receptors that may be worthy therapeutic targets or models include proteion kinase C isoforms, tyrosine phosphatases, CbI (which enhances EGF receptor turnover; alternative forms of erbB family receptors), and 'argos', a physiologic antagonist of the Drosophila EGF receptor [50*].

In tissue culture, ligand-independent activation of ErbB-2 is sufficient to transform cells even though overexpression of the EGF receptor has no effect [10]. Overexpression probably increases receptor phosphorylation and signaling by increasing the rate of inter-receptor collisions. Differences between transforming activities of ErbB-2 and the EGF receptor have been traced to specific portions of the intracellular domains, indicating that differential signaling qualities are important, and ErbB-2 may also be better at ligand-independent dimerization [51,52]. Overexpression of wild-type ErbB-2 in the mammary glands of transgenic mice induces metastatic breast cancer [9,53*]. This animal model revealed that carcinogenesis initiated by overexpression of ErbB-2 is a multistep process. Tumorigenicity requires additional structural alterations of ErbB-2, mutations in other oncogenes, or excessive production of EGF agonists [54,55,56]. The structural changes are small in-frame deletions just outside of the ErbB-2 transmembrane domain. These deletions leave unpaired cysteine residues that cause constitutive dimerization and transformation mediated by disulfide bonds. Although such deletions have not been identified in human tumors, a splice variant may achieve the same result.

Alternative forms of ErbB family receptors

Variant forms of EGF receptor, ErbB-2, and ErbB-3 can be produced as a result of differential splicing or proteolytic processing. Oncogenic forms of the EGF receptor have been described, albeit seldomly in breast cancer (for review [57, 58]). An alternative spliced form of ErbB-2 has also been described, in which the exon encoding protein sequences immediately preceding the transmembrance domain is skipped. The resulting polypeptide has an unpaired cysteine and, like the deletion-activated receptor in the mouse transgenic model, dimerizes constitutively and transforms cells [13**,59*]. Hence, this spliced variant mRNA may encode a subpopulation of ErbB-2 molecules that is primarily responsible for carcinogenesis.

Another set of variant molecules might be less active than the common receptor forms and dominantly inhibit signaling. Soluble extracellular domains of EGF receptor, ErbB-2, and ErbB-3 that are encoded by alternative spliced products may act as sinks or buffers that bind agonists [60,61]. They can be produced either through direct coding by spliced variant mRNAs, or through proteolytic processing of full-length receptors. One such molecule, 'herstatin', is encoded by a spliced isoform of ErbB-2, and disrupts ErbB-2 dimerization and signaling [62*].

Truncated receptors can also be produced through proteolytic cleavage of full-length molecules. Cleavage of the extracellular juxtamembrane domain would hypothetically yield a soluble ectodomain, which may function as an inhibitor, and concomitantly a truncated anchored receptor that would be constitutively active. Such an activated form of ErbB-2 is found in a subset of tumors that overexpress ErbB-2. It is apparently produced through cleavage by one or more metalloproteinases. This extracellularly truncated form is activated for signaling, and may be associated with lymph node metastasis [63*].

Other sources of signaling heterogeneity

The ligand-activated EGF receptor is downregulated through receptor-mediated endocytosis. ErbB-2, ErbB-3, and ErbB-4 show little ligand-dependent endocytosis compared with the EGF receptor [64*]. Once internalized, the EGF receptor may be degraded, or, alternatively, recycled to the cell surface. The strong downregulation of the EGF receptor occurs in part because it preferentially associates with the ring-finger protein Cbl, which in turn favors degradation [65**]. Stability and signaling of the EGF receptor may be further enhanced by overexpression of ErbB-2, providing another mechanism through which ErbB2 overexpression enhances signaling by the EGF receptor [66].

Autocrine and paracrine regulation of the receptors is probably of paramount importance in determining the amount of signal produced by overexpressed ErbB family receptors. Production of TGF-α, amphiregulin, and neuregulin have all been described in breast cancer (for review [21*]). The regulation of ErbB receptors on tumor cells may change during tumor progression, because the availability of paracrine ligands may change as tumors move out from the intraductal environment to invade locally and distantly.

Another consequence of hormonal stimulation is that it may qualititatively alter the signaling activity of the receptors. Different kinase-substrate pairs are juxtaposed in different receptor dimers, so that signaling by EGF receptor-ErbB2 heterodimers, for example, is different from the sum of signals emitted by the respective homomers. Differential positioning of receptors by different ligands may also influence signaling qualitatively [67*,68,69*].

ErbB receptors are sometimes jointly overexpressed in breast cancer, suggesting either that they cooperate in carcinogenesis, or that overexpression of one receptor upregulates expression of another. In transfection experiments, EGF receptor and ErbB2 synergize in cell transformation, which is consistent with the former model [24*]. Synergy may result from the ability of ErbB2 in heterodimers to stabilize ligand binding and impair EGF receptor turnover, as discussed above, to expand the repertoire of pathways activated, or to enhance the duration of signaling by the two receptors [19*,34**]. In MMTV-NEU transgenic mouse models, tumors express high levels of EGF receptor [70] or ErbB-3 [13]. The latter apparently results from post-transcriptional upregulation of ErbB-3 by ErbB-2 [53].

Clinical impact

From the perspective of the clinician, the knowledge that ErbB family receptors are altered in breast cancer is most important if it has prognostic value, if it can be used to make treatment decisions, or if the receptors or ligands are good therapeutic targets. The most extensive clinical data are available for ErbB-2. Amplification or overexpression of ErbB-2 is associated with accelerated relapse and mortality [3*] (for review [4*,71*]). Although ErbB-2 status is not currently in common use for breast cancer treatment decisions, it may be helpful in borderline situations. Because Herceptin is most likely to be valuable for patients with tumors that overexpress ErbB-2, such patients were selected for earlier clinical trials, and the drug is approved for use in the USA in this subset of patients.

Clinical tests that are based on fluorescent in situ hybridization or immunohistochemistry are typically used to identify ErbB-2 amplification or overexpression. As discussed above, signaling heterogeneity could significantly affect clinical changes associated with receptor overexpression and the response to therapeutic antagonists; whatever role an individual receptor plays in breast cancer, the clinical variables should correlate best with the signaling activity of the receptor, rather than with its abundance. The use of phosphorylation-sensitive antibodies that read out ErbB receptor phosphorylation at specific sites may be the broadest approach to contending with these competing forms of regulation, because the phosphorylation status of the receptors is a direct measure of their signaling activity [72,73]. Antibodies that recognize tyrosine phosphorylated (active) forms of ErbB-2 identify a subset of breast cancer patients with poor prognosis [74]. Better understanding and quantification of these variables should greatly augment the clinical utility of ErbB receptor status (for review [71*]).

The signaling diversity engendered by the different signaling activities of the four receptors means that activation of specific receptor combinations may be most strongly linked to tumor aggressiveness, whereas other may be associated with better prognosis. Thus, the most powerful clinical predictions may be obtained through quantification of different receptor activations, and the most powerful therapeutic strategies may work by targeting specific subsets of receptors. For example, the synergy of EGF receptor and ErbB2 in carcinogenesis has suggested the development of binary therapeutic agents targeting both receptors [75].

In both tissue culture and clinical studies, overexpression of ErbB receptors has been associated with resistance to specific chemotherapeutic agents [76]. Other studies have suggested that patients with ErbB-2-overexpressing tumors may benefit from high doses of chemotherapy. Finally, synergy has been observed between genotoxic drugs and EGF receptor or ErbB2 antagonists [77,78,79]. Because of discordances in the research literature, the extent and mechanisms of these phenomena are controversial, and the reader is referred to reviews of the subject [4*,71*,80*]. Nonetheless, the evidence clearly demonstrates that the deployment of ErbB-directed therapies can have significant impact on the response to other agents.

Changes in ErbB family receptors may also affect response to hormone therapy with estrogen antagonists. This may have major practical consequences as therapeutic agents targeting the ErbB receptors are produced, given the importance of hormone therapy in treating breast cancer. At least two molecular links have been established between estrogen receptor and ErbB receptors. Estrogen suppresses ErbB-2 transcription and expression [81*], and, conversely, the antagonist tamoxifen has the undesirable property of augmenting ErbB2 expression [82*]. ErbB receptors themselves regulate estrogen-signaling pathways, either by directly phosphorylating the estrogen receptor, or by activating mitogen-activated protein kinases, which in turn enhance estrogen receptor signaling [83*,84*].

Conclusion

The ErbB family of receptors are outstanding targets for breast cancer therapies (and diagnosis). Optimal clinical performance of ErbB-targeted reagents will best be achieved by harnessing knowledge about the biologic activities of these receptors in the mammary gland. Although the fundamentals of ligand regulation of these receptors have been established, there is still much to be learned. Work in Drosophila melanogaster suggests that fine tuning of expression and processing of ligands and receptors, along with the operation of natural antagonists, will be important for normal regulation [85*]. The association of specific signaling pathways with receptor-specific functions is not well understood. Finally, understanding the mechanism of action of Herceptin (for review [86*]) may lead to improved second-generation therapeutics.

References

  1. Cobleigh M, Vogel C, Tripathy D, et al: Efficacy and safety of Herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer. In: Proceedings of the American Society of Clinical Oncology; Thirty-fourth Annual Meeting. Los Angeles, CA: WB Saunders Co. 1998

    Google Scholar 

  2. Slamon D, Leyland-Jones B, Shak S, et al: Addition of Herceptin (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2 +/MBC) markedly increases anticancer activity: a randomized multinational controlled phase III trial. In: American Society of Clinical Oncology; Thirty-fourth Annual Meeting. Los Angeles, CA: WB Saunders Co. 1998

    Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. Hynes NE, Stern DF: The biology of erbB-2/neu/HER-2 and its role in cancer. Biochem Biophys Acta Rev Cancer. 1994, 1198: 165-184. 10.1016/0304-419X(94)90012-4.

    Article  Google Scholar 

  5. van de Vijver MJ, Peterse JL, Mooi WJ, et al: Neu-protein overexpression in breast cancer: association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med. 1988, 319: 1239-1245.

    Article  CAS  PubMed  Google Scholar 

  6. Bates N, Hurst H: Transcriptional regulation of Type I receptor tyrosine kinases in the mammary gland. J Mammary Gland Biol Neoplasia. 1997, 2: 153-163. 10.1023/A:1026303814855.

    Article  CAS  PubMed  Google Scholar 

  7. Pollack J, Perou C, Alizadeh A, et al: Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nature Genet. 1999, 23: 41-46. 10.1038/14385.

    Article  CAS  PubMed  Google Scholar 

  8. Stein D, Wu J, Fuqua SAW, et al: The SH2 domain protein GRB-7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer. EMBO J. 1994, 13: 1331-1340.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Guy CT, Webster MA, Scheller M, et al: Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA. 1992, 89: 10578-10582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Difiore P, Pierce J, Kraus M, et al: ErbB-2 is a potent oncogene when overexpressed in NIH3T3 cells. Science. 1987, 237: 179-182.

    Google Scholar 

  11. Klijn J, Berns P, Schmitz P, Foekens J: The clinical significance of epidermal growth factor receptor (EFG-R) in human breast cancer: a review on 5232 patients. Endocr Rev. 1992, 13: 3-17. 10.1210/er.13.1.3.

    CAS  PubMed  Google Scholar 

  12. Travis A, Pinder S, Robertson J, et al: c-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. Br J Cancer. 1996, 74: 229-233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Siegal P, Ryan E, Cardiff R, Muller W: Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBO J. 1999, 18: 49-64. 10.1093/emboj/18.1.49.

    Article  Google Scholar 

  14. Lemoine NR, Barnes DM, Hollywood DP, et al: Expression of the ERBB3 gene product in breast cancer. Br J Cancer. 1992, 66: 1116-1121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Srinivasan R, Poulsom R, Hurst H, Gullick W: Expression of the c-erbB-4/HER4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types. J Pathol. 1997, 185: 236-245. 10.1002/(SICI)1096-9896(199807)185:3<236::AID-PATH118>3.0.CO;2-7.

    Article  Google Scholar 

  16. Vogt U, Bielawski K, Schlotter C, et al: Amplification of erbB-4 oncogene occurs less frequently than that of erbB-2 in primary human breast cancer. Gene. 1998, 223: 375-380. 10.1016/S0378-1119(98)00454-5.

    Article  CAS  PubMed  Google Scholar 

  17. Bacus SS, Chin D, Zelnick CR, Stern DF: Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors. Am J Pathol. 1996, 148: 549-558.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Knowlden J, Gee J, Seery L, et al: c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer. Oncogene. 1998, 17: 1949-1957. 10.1038/sj/onc/1202107.

    Article  CAS  PubMed  Google Scholar 

  19. Riese DJ, Stern DF: Specificity within the EGF/ErbB receptor family signaling network. BioEssays. 1998, 20: 41-48. 10.1002/(SICI)1521-1878(199801)20:1<41::AID-BIES7>3.0.CO;2-V.

    Article  PubMed  Google Scholar 

  20. Klapper L, Glathe S, Vaisman N, et al: The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci USA. 1999, 96: 4995-5000. 10.1073/pnas.96.9.4995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Salomon D, Brandt R, Ciardiello F, Normanno N: Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995, 19: 183-232. 10.1016/1040-8428(94)00144-I.

    Article  CAS  PubMed  Google Scholar 

  22. Prenzel N, Zwick E, Leserer M, Ullrich A: Tyrosine kinase signalling in breast cancer: Epidermal growth factor receptor: convergence point for signal integration and diversification. Breast Cancer Res. 2000, 2: in-press. 10.1186/bcr52.

    Article  Google Scholar 

  23. Riese DJ, van Raaij TM, Plowman GD, Andrews GC, Stern DF: Cellular response to neuregulins is governed by complex interactions of the erbB receptor family. Mol Cell Biol. 1958, 15: 5770-5776.

    Article  Google Scholar 

  24. Kokai Y, Meyers JN, Wada T, et al: Synergistic interaction of p185 c-neu and the EGF receptor leads to transformation of rodent fibroblasts. Cell. 1989, 58: 287-292.

    Article  CAS  PubMed  Google Scholar 

  25. Karunagaran D, Tzahar E, Beerli R, et al: ErbB2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J. 1996, 15: 254-264.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Guy PM, Platko JV, Cantley LC, Cerione RA, Carraway KL: Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci USA. 1994, 91: 8132-8136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Stern DF, Kamps MP: EGF-stimulated tyrosine phosphorylation of p185neu: a potential model for recetor interactions. EMBO J. 1988, 7: 995-1001.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Tzahar E, Waterman H, Chen X, et al: A hierarchical network of interreceptor interactions determines signal transduction by new differentation factor/neuregulin and epidermal growth factor. MOL Cell Biol. 1996, 16: 5276-5287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. DiFiore PP, Segatto O, Lonardo F, et al: The carboxyl-terminal domains of erbB-2 and epidermal growth factor receptor exert different regulatory effects on intrinsic receptor tyrosine kinase function and transforming activity. Mol Cell Biol. 1990, 10: 2749-2756.

    Article  CAS  Google Scholar 

  30. Kim H-H, Sierke S, Koland J: Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. J Biol Chem. 1994, 269: 24747-24755.

    CAS  PubMed  Google Scholar 

  31. Daly J, Jannot C, Beerli R, et al: Neu differentiation factor induces ErbB2 down-regulation and apoptosis of ErbB2-overexpressing breast tumor cells. Cancer Res. 1997, 57: 3804-3811.

    CAS  PubMed  Google Scholar 

  32. Bacus SS, Huberman E, Chin D, et al: A ligand for the erbB-2 oncogene product (gp30) induces differentiation of human breast cancer cells. Cell Growth Differ. 1992, 3: 401-411.

    CAS  PubMed  Google Scholar 

  33. Jones FE, Jerry DJ, Guarino BC, Andrews GC, Stern DF: Heregulin induces in vivo proliferation and differentiation of mammary epithelium into secretory lobuloaveoli. Cell Growth Differ. 1996, 7: 1031-1038.

    CAS  PubMed  Google Scholar 

  34. Graus-Porta D, Beerli RR, Hynes NE: Single-chain antibody-mediated intracellular retention of erbB-2 impairs neu differentiation factor and epidermal growth factor signaling. Mol Cell Biol. 1995, 15: 1182-1191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dickson C, Spencer-Dene B, Dilon C, Fantl V: Tyrosine kinase signalling in breast cancer: Fibroblast growth factors and their receptors. Breast Cancer Res. 2000, 2: in-press. 10.1186/bcr53.

    Article  Google Scholar 

  36. Yang Y, Spitzer E, Meyer D, et al: Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland. J Cell Biol. 1995, 131: 215-226.

    Article  CAS  PubMed  Google Scholar 

  37. Sebastian J, Richards RG, Walker MP, et al: Activation and function of the epidermal growth factor receptor and erbB-2 during mammary gland morphogenesis. Cell Growth Differ. 1998, 9: 777-785.

    CAS  PubMed  Google Scholar 

  38. Schroeder JA, Lee DC: Dynamic expression and activation of ERBB receptors in the developing mouse mammary gland. Cell Growth Differ. 1998, 9: 451-464.

    CAS  PubMed  Google Scholar 

  39. Gassmann M, Casagranda F, Orioli D, et al: Aberrant neural and cardiac developement in mice lacking the ErbB4 neuregulin receptor. Nature. 1995, 378: 390-394. 10.1038/378390a0.

    Article  CAS  PubMed  Google Scholar 

  40. Lee K-F, Simon H, Chen H, et al: Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature. 1995, 378: 394-398. 10.1038/378394a0.

    Article  CAS  PubMed  Google Scholar 

  41. Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, et al: Severe neuropathies in mice with targeted mutation in the ErbB3 receptor. Nature. 1997, 389: 725-730. 10.1038/39593.

    Article  CAS  PubMed  Google Scholar 

  42. Xie W, Paterson A, Chin E, Nabell L, Kudlow J: Targeted expression of a dominant negative epidermal growth factor receptor in the mammary gland of transgenic mice inhibits pubertal mammary duct development. Mol Endocrinol. 1997, 1: 1766-1781. 10.1210/me.11.12.1766.

    Article  Google Scholar 

  43. Wiesen J, Young P, Werb Z, Cunha G: Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development. Development. 1999, 126: 335-344.

    CAS  PubMed  Google Scholar 

  44. Jones F, Stern D: Expression of dominant-negative ErbB2 in the mammary gland of transgenic mice reveals a role in lobuloalveolar development and lactation. Oncogene. 1999, 18: 3481-3490. 10.1038/sj/onc/1202698.

    Article  CAS  PubMed  Google Scholar 

  45. Jones FE, Welte T, Fu X-Y, Stern DF: ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation. J Cell Biol. 1999, 147: 77-88. 10.1083/jcb.147.1.77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Niemann C, Brinkamann V, Spitzer E, et al: Reconstitution of mammary gland development in vitro: requirement of c-met and c-erbB2 signaling for branching and alveolar morphogenesis. J Cell Biol. 1998, 143: 533-545. 10.1083/jcb.143.2.533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kenney NJ, Huang RP, Johnson GR, et al: Detection and location of amphiregulin and cripto-1 expression in the developing postnatal mouse mammary gland. Mol Reprod Dev. 1995, 41: 277-286. 10.1262/jrd.41.277.

    Article  CAS  PubMed  Google Scholar 

  48. Luetteke N, Qiu T, Fenton S, et al: Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Developement. 1999, 126: 2739-2750.

    CAS  Google Scholar 

  49. Coleman S, Silberstein GB, Daniel CW: Ductal morphogenesis in the mouse mammary gland: evidence supporting a role for epidermal growth factor. Dev Biol. 1988, 127: 304-315.

    Article  CAS  PubMed  Google Scholar 

  50. Schweitzer R, Howes R, Smith R, Shilo B-Z, Freeman M: Inhibition of Drosophila EGF receptor activation by the secreted protein Argos. Nature. 1995, 376: 699-702. 10.1038/376699a0.

    Article  CAS  PubMed  Google Scholar 

  51. DiFiore P, Pierce J, Fleming T, et al: Overexpression of the human EGF receptor confers and EGF-dependent transformed phenotype to HIH 3T3 cells. Cell. 1987, 51: 1063-1070.

    Article  CAS  Google Scholar 

  52. Burke CL, Stern DF: Activation of Neu (ErbB-2) mediated by disulfide bond-induced dimerization reveals a receptor tyrosine kinase dimer interface. Mol Cell Biol. 1998, 18: 5371-5379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Andrechek ER, Muller WJ: Tyrosine kinase-mediated signal transduction in transgenic mouse models of human breast cancer. Breast Cancer Res. 2000

    Google Scholar 

  54. Siegel PM, Dankort DL, Hardy WR, Muller WJ: Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. Mol Cell Biol. 1994, 14: 7068-7077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Li B, Rosen J, McMenamin-Balano J, Muller M, Perkins A: neu/ERBB2 cooperates with p53-172H during mammary tumorigenesis in transgenic mice. Mol Cell Biol. 1997, 17: 3155-3163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Muller WJ, Arteaga C, Muthuswamy S, et al: Synergistic Interaction of the Neu proto-oncogene product and transforming growth factor α in the mammary epithelium of transgenic mice. Mol Cell Biol. 1996, 16: 5726-5736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Moscatello D, Holgado-Madruga M, Godwin A, et al: Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res. 1995, 55: 5536-5539.

    CAS  PubMed  Google Scholar 

  58. Carter T, Kung HJ: Tissue specific transformation by oncogenic mutants of epidermal growth factor receptor. Crit Rev Oncogen. 1994, 5: 389-428.

    Article  CAS  Google Scholar 

  59. Kwong K, Hung M: A novel splice variant of HER2 with increased transformation activity. Mol Carcinogen. 1998, 23: 62-68. 10.1002/(SICI)1098-2744(199810)23:2<62::AID-MC2>3.0.CO;2-O.

    Article  CAS  Google Scholar 

  60. Petch L, Harris J, Raymond V, et al: A truncated, secreted form of the epidermal growth factor receptor is encoded by an alternatively spliced transcript in normal rat tissue. Mol Cell Biol. 1990, 10: 2973-2982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Scott G, Robles R, Park J, et al: A truncated intracellular HER2/neu receptor produced by alternative RNA processing affects growth of human carcinoma cells. Mol Cell Biol. 1993, 13: 2247-2257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Doherty J, Bond C, Jardim A, Adelman J, Clinton G: The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proc Natl Acad Sci USA. 1999, 96: 10869-10874. 10.1073/pnas.96.19.10869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Christianson T, Doherty J, Lin Y, et al: NH2-terminally truncated HER-2/neu protein: relationship with shedding of the extracellular domain and with prognostic factors in breast cancer. Cancer Res. 1998, 58: 5123-5129.

    CAS  PubMed  Google Scholar 

  64. Baulida J, Kraus M, Alimandi M, Di Fiore P, Carpenter G: All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J Biol Chem. 1996, 271: 5251-5257. 10.1074/jbc.271.31.18989.

    Article  CAS  PubMed  Google Scholar 

  65. Levkowitz G, Waterman H, Zamir E, et al: c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev. 1998, 12: 3663-3674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Huang G, Chantry A, Epstein RJ: Overexpression of ErbB2 impairs ligand-dependent downregulation of epidermal growth factor receptors via a post-transcriptional mechanism. J Cell Biochem. 1999, 74: 23-30. 10.1002/(SICI)1097-4644(19990701)74:1<23::AID-JCB3>3.3.CO;2-C.

    Article  CAS  PubMed  Google Scholar 

  67. Crovello C, Lai C, Cantley L, Carraway K: Differential signaling by the epidermal growth factor-like growth factors neuregulin-1 and neuregulin-2. J Biol Chem. 1998, 273: 26954-26951. 10.1074/jbc.273.41.26954.

    Article  CAS  PubMed  Google Scholar 

  68. Olayioye M, Graus-Porta D, Beerli R, et al: ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol Cell Biol. 1998, 18: 5042-5051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Muthuswamy S, Gilman M, Brugge J: Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol. 1999, 19: 6845-6857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. DiGiovanna M, Lerman M, Coffey R, et al: Active signaling by Neu in transgenic mice. Oncogene. 1998, 17: 1877-1884. 10.1038/sj/onc/1202091.

    Article  CAS  PubMed  Google Scholar 

  71. DiGiovanna MP: Clinical significance of HER-2/neu overexpression: part II. In: Principles and Practice of Oncology Updates, Vol 13no 10. Edited by Rosenberg SA. Cedar Knolls: Lippincott Williams & Wilkins,. 1999, : 1-14.

    Google Scholar 

  72. DiGiovanna MP, Stern DF: Activation state specific monoclonal antibody detects tyrosine phosphorylated p185neu/erbB-2 in a subset of human breast tumors overexpressing this receptor. Cancer Res. 1995, 55: 1946-1955.

    CAS  PubMed  Google Scholar 

  73. DiGiovanna MP, Carter D, Flynn SD, Stern DF: Functional assay for HER-2/neu demonstrates active signaling in a minority of HER-2/neu overexpressing invasive human breast tumors. Br J Cancer. 1996, 74: 802-806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Thor A, Liu S, Edgerton S, et al: Activation (tyrosine phosphorylation) of ErbB-2 (HER2/neu) as a prognostic factor in node positive breast cancer. J Clin Oncol. 2000, : in-press.

    Google Scholar 

  75. Ye D, Mendelsohn J, Fan Z: Augmentation of a humanized anti-HER2 mAb 4D5 induced growth inhibition by a human-mouse chimeric anti-EGF receptor mAb C225. Oncogene. 1999, 18: 731-738. 10.1038/sj/onc/1202319.

    Article  CAS  PubMed  Google Scholar 

  76. Pegram M, Finn R, Arzoo K, et al: The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene. 1997, 15: 537-547. 10.1038/sj/onc/1201222.

    Article  CAS  PubMed  Google Scholar 

  77. Pietras R, Fendly B, Chazin V, et al: Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and overian cancer cells. Oncogene. 1993, 9: 1829-1838.

    Google Scholar 

  78. Aboud-Pirak E, Hurwitz E, Pirak M, et al: Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma, in vitro and in nude mice. J Natl Cancer Inst. 1988, 80: 1605-1611.

    Article  CAS  PubMed  Google Scholar 

  79. Arteaga C, Winnier A, Poirier M, et al: p185c-erbB-2 signaling enhances cisplatin-induced cytotoxicity in human breast carcinoma cells: association between an oncogenic receptor tyrosine kinase and drug-induced DNA repair. Cancer Res. 1994, 54: 3758-3765.

    CAS  PubMed  Google Scholar 

  80. Baselga J, Mendelsohn J: Receptor blockade with monoclonal antibodies as anti-cancer therapy. Pharmacol Ther. 1994, 64: 127-154. 10.1016/0163-7258(94)90036-1.

    Article  CAS  PubMed  Google Scholar 

  81. Read LD, Keith D, Slamon DJ, Katzenellenbogen BS: Hormonal modulation of HER-2/neu proto-oncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines. Cancer Res. 1990, 50: 3947-3951.

    CAS  PubMed  Google Scholar 

  82. Antoniotti S, Maggiora P, Dati C, DeBortoli M: Tamoxifen up-regulates c-erbB-2 expression in oestrogen-responsive breast cancer cells in vitro. Eur J Cancer. 1992, 28: 318-321.

    Article  CAS  PubMed  Google Scholar 

  83. Kato S, Endoh H, Masuhiro Y, et al: Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995, 270: 1491-1494.

    Article  CAS  PubMed  Google Scholar 

  84. Pietras RJ, Arboleda J, Reese DM, et al: HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene. 1995, 10: 2435-2446.

    CAS  PubMed  Google Scholar 

  85. Perrimon N, Perkins L: There must be 50 ways to rule the signal: the case of the Drosophila EGF receptor. Cell. 1997, 89: 13-16. 10.1016/S0092-8674(00)80177-4.

    Article  CAS  PubMed  Google Scholar 

  86. Sliwkowski M, Lofgren J, Lewis G, et al: Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 1999, 26: 60-70.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Michael DiGiovanna for reading the manuscript. This work was supported by United States Public Health Service grant R01CA45708 from the National Cancer Institute. We regret that space constraints permitted us to cite only a small sample of the extensive literature in this area.

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Stern, D.F. Tyrosine kinase signalling in breast cancer: ErbB family receptor tyrosine kinases. Breast Cancer Res 2, 176 (2000). https://0-doi-org.brum.beds.ac.uk/10.1186/bcr51

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