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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Clin Cancer Res. Author manuscript; available in PMC Mar 1, 2011.
Published in final edited form as:
PMCID: PMC2831167
NIHMSID: NIHMS159581
HER3 comes of age; New insights into its functions and role in signaling, tumor biology, and cancer therapy
Marcia R. Campbell,* Dhara Amin,* and Mark M. Moasser
Department of Medicine & Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143
Correspondence: Mark M. Moasser University of California, San Francisco Box 1387 San Francisco, CA 94143-1387 Tel: 415-476-0158 ; mark.moasser/at/ucsf.edu
*These authors contributed equally.
The human epidermal growth family (HER) of tyrosine kinase receptors underly the pathogenesis of many types of human cancer. The oncogenic functions of three of the HER proteins can be unleashed through amplification, overexpression, or mutational activation. This has formed the basis for the development of clinically active targeted therapies. However, the third member HER3 is catalytically inactive, not found to be mutated or amplified in cancers, and its role and functions have remained shrouded in mystery. Recent evidence derived primarily from experimental models now appear to implicate HER3 in the pathogenesis of several types of cancer. Furthermore, the failure to recognize the central role of HER3 appears to underly resistance to EGFR or HER2 targeted therapies in some cancers. Structural and biochemical studies have now greatly enhanced our understanding of signaling in the HER family and revealed the previously unrecognized activating functions embodied in the catalytically impaired kinase domain of HER3. This renewed interest and mechanistic basis has fueled the development of new classes of HER3-targeting agents for cancer therapy. However, identifying HER3-dependent tumors presents a formidable challenge and the success of HER3-targeting approaches depend entirely on the development and power of predictive tools.
The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) are the most extensively studied family of RTKs and strongly implicated in the pathogenesis of many types of human cancer. The family includes the four highly homologous members EGFR (HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4), sharing a structure that consists of a ligand-binding extracellular domain (ECD), an intracellular kinase domain (KD), and a c-terminal signaling tail. Signaling is mediated through ligand-induced receptor dimerization and transphosphorylation, leading to activation of cytoplasmic signaling pathways. The individual HER proteins have non-redundant functions and unique attributes and heterodimerization constitutes the predominant mode of signaling in this family. The functions of the third member HER3 have been least understood, and mounting evidence implicating it in human cancer pathogenesis have deepened interest in resolving the mysteries surrounding it.
The unique attribute that separates HER3 from the other HER proteins is its evolutionary divergence at critical residues within the KD, locking it in the inactive conformation, thus devoid of catalytic kinase activity (1-3). Our traditional models of RTK function have not been able to deal with this finding, and by default, HER3 has been considered to function merely as a signaling substrate for other HER proteins, analogous to the functions of IRS1 and IRS2 with the insulin receptor. This model would appear to dismiss functionality within the HER3 KD, a concept that is difficult to reconcile in evolutionary terms. The recent landmark study revealing a highly unique mechanism underlying KD activation in the HER family now finally identifies the potential functions of a catalytically inactive KD such as that of HER3. In the HER family, dimerization of the KDs occurs in an asymmetric configuration leading to the allosteric activation of one KD by the other (4). In this interaction the “activator” KD has no catalytic role, immediately suggesting that the HER3 KD may be a highly specialized allosteric activator of its HER family partners (figure 1a). The functions of the HER3 KD as a specialized allosteric activator have been confirmed in biochemical assays (3).
Figure 1a
Figure 1a
Schematic representation of HER3 engaged in dimerization and actively signaling. The dimer is reinforced by interaction of the juxta-membrane segments, forming a stabilizing latch. Through its activating interface, HER3 engages and allosterically activates (more ...)
In contrast to the other HER proteins, HER3 is not transforming when overexpressed or constitutively activated by continuous ligand stimulation (5) and there are currently no mutational alterations known to confer oncogenic activities to HER3. This may be due to a number of mechanisms in place that appear to function to restrain the signaling functions of HER3 (figure 1b). The absence of catalytic activity is only one such mechanism. In the absence of ligand activation, the HER3 c-terminal tail binds and covers its activation surface in trans, restraining its allosteric activation functions (3). In addition, the clustering of HER3, based on both ECD interactions and ICD interactions, appears to provide yet additional restraint through its sequestration away from EGFR and HER2 (3, 6). HER4 may also participate in HER3 sequestration, providing some insight into why increased HER4 expression has been found to be associated with a less malignant biology in breast cancers (3). Additionally, the Ebp-1 protein has been known to interact with a region of HER3 that was recently identified as the dimer-stabilizing juxtamembrane region (7, 8). As such, Ebp-1 binding may potentially function to prevent premature dimerization, providing yet another mechanism nature has provided to restrain HER3 from inappropriately activating its HER partners.
Figure 1b
Figure 1b
Schematic representation of mechanisms in place that restrain HER3 from signaling. If not transcriptionally, post-transcriptionally, or post-translationally repressed, much of HER3 is sequestered into clusters mediated through N-lobe head-to-head interactions (more ...)
When the restraints on HER3 are lifted, HER3 functions not only as a specialized allosteric activator of other HER proteins, but also as their signaling substrate. The 14 tyrosines in the c-terminal signaling tail of HER3, when phosphorylated, can potentially dock numerous SH2 or PTB binding proteins involved in a number of different intracellular signaling pathways (figure 1c). Whether all of these tyrosines are phosphorylated in cells, and whether all of the described interactions are physiologically relevant remain to be defined. But the one critically important and well established signaling activity of HER3 is its unique and potent ability to activate downstream PI3K and Akt pathway signaling by virtue of six concensus phosphotyrosine sites, not present on EGFR or HER2, which bind the SH2 domain of the three regulatory subunits of PI3K (9-11)(figure 1c). Activated PI3K phosphorylates membrane phosphoinositides, leading to recruitment and activation of PDK1 and Akt. Akt lies at the hub of a plethora of downstream pathways, in particular in an intricate upstream and downstream relationship with two mTor-containing complexes, and is in a position to control many biological processes critical for tumorigenesis including translation, survival, nutrient sensing, metabolic regulation, and cell cycle control (12)(figure 1a).
Figure 1c
Figure 1c
Schematic depiction of the 14 tyrosines on the c-terminal signaling tail of HER3. Whether or not all of these tyrosines undergo phosphorylation in cells has not been confirmed. But phospho-peptide binding studies have identified many SH2 and PTB domains (more ...)
The link between HER3 and the Akt pathway not only confers oncogenic capabilities to its kinase-active HER family partners, but provides a signaling node that can potentially be exploited by other signaling pathways to engage the activities of Akt. Most tumors require PI3K/Akt signaling for their survival, and this is often achieved by upstream receptor tyrosine overactivity, by mutational activation of PI3K or inactivation of PTEN. However the induction of HER3 provides another pathway towards this end, and indeed the expression of HER3 appears to be more dynamic than other HER proteins and inducible when required. The finding that the induction of HER3 expression or signaling is associated with drug resistance in several cancer models supports such a role. HER3 expression or signaling is associated with resistance to HER2 inhibitors in HER2-amplified breast cancers (13), with EGFR inhibitors in lung cancers (14), with pertuzumab resistance in ovarian cancers (15), with anti-estrogen therapies in ER-positive breast cancers (16-19), with EGFR inhibitors in head & neck cancers (20),with hormone resistance in prostate cancers (21), and with IGF1R inhibitors in hepatomas (22). In most of these scenarios, it is assumed that HER3 phosphorylation is driven by one of its HER family kinase partners. A more promiscuous role for HER3 as a substrate of other kinases is possible, and at least suggested by the c-MET induced activation of HER3 signaling (14), however this has not been directly demonstrated.
The cellular signals that regulate HER3 expression are only beginning to be identified. HER3 protein expression is regulated by both transcriptional and post-transcriptional mechanisms. Post-transcriptionally, it is regulated by the E3 ligase Nrdp1 and the Nrdp1 regulator USP8 (23). USP8 in turn is regulated by Akt and this pathway potentially links HER3 expression with downstream Akt activity constituting the potential reciprocal regulation of HER3 expression with Akt activity. The transmembrane protein LRIG1 is another negative regulator of growth factor receptor signaling. It associates with all four HER family members, although current studies have only addressed its role in the specific regulation of EGFR and HER2 (24-26). The transmembrane mucin MUC4 alters HER2 and HER3 trafficking, stabilizes their membrane localization, consequently increasing their signaling functions (27). HER3 is also regulated transcriptionally, as seen in response to TKI treatment of HER2-amplified breast cancer cells ((13) and manuscript in submission). The expression of HER3 is also under regulation by several miRNAs identified thus far, including miR205, miR125a, and miR125b (28, 29).
The precise functional relevance of HER3 across the spectrum of human cancers remains largely unknown at this time. There is solid mechanistic and experimental evidence supporting its tumor promoting functions in subsets of breast and lung cancers, as well as a body of more speculative, descriptive, and sometimes conflicting data in many other cancers. The existing literature regarding the expression and relevance of HER3 in human cancers is summarized in Table 1. The data sets vary considerably in their methodologies and can not be easily compared. While some investigators analyze expression, others analyze over-expression relative to normal tissues or within the sample sets. There is also great variance in the reported localization of HER3, including nuclear expression on IHC studies, and these should be interpreted with caution until confirmed by the appropriate biochemical studies.
Table thumbnail
Experimental evidence has solidly established the critical role of HER3 as a co-receptor for the amplified HER2 oncogene, most commonly seen in breast cancers, but also in a variety of other tumor types. Although HER3 is not transforming by itself, it is synergistically co-transforming with HER2 (30). In fact, the expression of HER3 is rate-limiting for HER2-induced transformed growth and if HER3 expression is knocked down, HER2-amplified tumors cease to grow and undergo apoptotic cell death (31, 32). Considering that HER2 expression is generally a constant in this tumor type, the regulated expression of HER3 functions as a volume control for HER2-HER3 signaling. This rheostat function is exemplified during attempts to inhibit HER2-HER3 signaling with tyrosine kinase inhibitors (TKIs). Treatment of HER2-amplified breast cancers with HER2-targeting TKIs leads to a rapid compensatory increase in HER3 expression, localization, and signaling activity, revealing a significant reserve capacity embodied within the HER2-HER3 signaling complex that renders it highly resilient to anti-cancer therapies (13). In this context, HER3 is the both the allosteric activator of HER2 kinase as well as its critical signaling substrate, and as such functions both upstream and downstream of HER2, redefining the HER2-HER3 complex as the functionally relevant oncogenic driver of the disease.
Other lines of evidence also demonstrate an important role for HER3 as a co-receptor for EGFR in a subset of lung cancers. In a comparison of lung cancer cell lines that are sensitive or resistant to the EGFR TKI gefitinib, the best marker of sensitivity to gefitinib appears to be the HER3-dependent activation of PI3K (33). This EGFR-HER3 interdependency is seen in tumor cell types harboring mutationally activated EGFR as well as wild-type EGFR, revealing a central role for EGFR-HER3 signaling in this disease. Treatment of patients with gefitinib is highly effective in these patients, although the development of acquired resistance is universal. While resistance typically develops as a result of secondary mutational events within the EGFR kinase domain rendering EGFR drug-resistant, rarely resistance can also develop through overactivity of the cooperating proto-oncogene c-MET and the c-MET-dependent phosphorylation of HER3, further highlighting the central role of HER3 in the pathogenesis of this disease (14).
There is a mounting body of evidence that implicates HER3 and the HER family in the pathogenesis of melanoma. HER3 is not expressed in normal melanocytes, but HER3 expression is seen in many malignant melanomas and is associated with more advanced stage, increased proliferation, and decreased survival (34, 35). This suggests that HER3 may be important in melanoma progression, and experimental models of HER3 knockdown suggest a role in migration and invasion (35, 36). The HER kinase partner for HER3 in melanomas is not well identified at this time. HER2 is not commonly expressed in melanomas, but EGFR is widely expressed and HER4 is mutationally activated in a subset of melanomas (36-39). The evidence that HER3 may be functionally important in melanoma is mounting, but much more work needs to be done to confirm and define its role.
EGFR targeting therapies show clinical activity in colon cancers, but the mechanistic basis for this activity remains undefined. Several studies looking at the expression of HER family members have produced largely conflicting and overall inconclusive results. However a recent mouse conditional model reveals that loss of HER3 in the intestinal epithelium leads to the concomitant loss of HER4 and prevention of tumorigenesis in ApcMin mice (40). These results were also reproduced in human colon cancer cells and will undoubtedly lead to much further analysis of colon cancers, focusing on HER3 and HER4. HER3 expression in ovarian cancers is associated with decreased survival and with resistance to the HER2-targeting mAb pertuzumab (15, 41), suggesting a functionally relevant role for HER3 in a subset of ovarian cancers. HER3 expression is upregulated in clear cell sarcomas of soft tissue and the receptor activated by autocrine neuregulin expression in many of them (42, 43).
The important role of HER3 as a signaling hub for the HER3 family has identified it as a candidate target for drug discovery and numerous HER3-targeting programs are currently underway to explore the potential of this new target. But HER3-targeting initiatives are faced with some unique challenges, both in the technical and strategic realms.
A principal technical challenge concerns what functionality of HER3 to target. Unlike the other HER family members, the functions of HER3 are not mediated through enzymatic catalytic activity and at this point, it does not seem that the ATP analog class of tyrosine kinase inhibitors would be suitable for this target. Whether ATP binding is required or plays a role in the stimulatory function or stability of the HER3 KD remains to be determined. If ATP is indeed found to be required for this function, this could lead to the development of ATP analog drugs that target non-catalytic functions, sometimes referred to as “pseudokinase” inhibitors. The stimulatory functions of the HER3 KD can also be targeted with newer classes of allosteric inhibitors. These could potentially target the KD dimerization interface, preventing the allosteric activation of EGFR or HER2 by HER3, or they could target the juxtamembrane latch, destabilizing the dimerized conformation of the HER3 KD. Much of the functions of the HER3 KD are still shrouded in mystery and the endeavor to target the functions of the HER3 KD require exploratory and potentially pioneering work into unchartered waters, and their products would be first-in-class molecules. Although risky as investments, such class inventions can lead to advances in targeted therapies that extend far beyond the realm of HER3.
Targeting the extracellular domain of HER3 with macromolecules such as antibodies is much more amenable to existing well established pharmaceutical platforms and several such programs are currently underway. Inherent in this approach are also some uncertainties regarding the optimal activity to be targeted by antibodies. The most traditional approach with transmembrane receptors has been to target a region that interferes with ligand binding and ligand-induced activation. The success of such a treatment hypothesis depends on an underlying assumption that it is the ligand-activated conformation of HER3 that is the driving force in tumor progression. The validity of this assumption is not at all certain and may indeed vary among different cancer subtypes and even among individual patients tumors. The anti-HER2 monoclonal antibody pertuzumab was developed to target the dimerization interface of HER2 and disrupt ligand-induced HER2-HER3 dimerization and signaling. While pertuzumab appears to be quite effective at inhibiting neuregulin-induced HER3 signaling (32, 44), it appears to be much less effective at disrupting the elevated basal state of ligand-independent HER2-HER3 interaction and signaling in HER2-overexpressing tumor cells (45, 46). This is not surprising as liganded and unliganded conformations of the HER3 ECD have very different structural characteristics. The nature of the physical interaction that underlies HER2-HER3 transactivation in the absence of ligand are not well understood, and at this point “ligand-independent signaling” remains a concept without a structural descriptor, although several hypotheses regarding this interaction can be proposed.
The major strategic challenge in the development of HER3-targeting agents is predicting patient populations and disease subtypes that would be amenable to this treatment modality. Unlike other targets, the tumor-promoting functions of HER3 are not harnessed through its over-expression, amplification, or mutation, making it more difficult to identify HER3-dependent tumors. At this point, a critical function for HER3 has been confirmed in HER2-amplified breast cancers, and strongly implicated in a subset of EGFR-driven lung cancers. The best marker to identify the functional relevance of HER3 in other tumors is the detection of phosphorylated HER3, which is the principal reporter of HER3 signaling. Numerous antibody reagents are available that detect phosphorylated HER3 tyrosine residues on western blots, however a reagent that can reliably detect p-HER3 in formalin-fixed paraffin-embedded tissues has been a challenge to develop. There are limited published reports containing p-HER3 immunostaining data using available commercial reagents (34). However in our hands, these same reagents fail the test of p-HER3 specificity when assayed using positive (ligand-stimulated) and negative (TKI-treated) control cell lines which are fixed in formalin and embedded in paraffin. The success of HER3-targeting therapies is entirely dependent on the validity of the p-HER3 biomarker assays and the validity and reliability of such assays is of utmost importance.
Another potential marker of HER3 signaling activity is the expression of its ligands in the tumor microenvironment. However this requires highly sensitive validated antibody reagents with specificity controls capable of detecting very dilute concentrations of the target ligands within the extracellular matrix. While this may be implausible, as a surrogate, most studies have attempted to indirectly assay ligand activity by immunostaining their transmembrane precursors in tumor cells. This approach discounts the role of stromal derived ligands, as well as proteolytic cleavage as a limiting and regulatory step in ligand release, while also appealing to the ongoing controversial proposition that membrane-bound ligand is competent and active at signaling. Most of these studies report frequent expression of neuregulins in tumors and were reviewed recently in the Molecular Pathways series (47). The data sets vary considerably with regards to membrane, cytoplasmic, nuclear, or stromal expression, and the true specificities of the signals are difficult to know, specially in light of universal expression reported by some studies.
While structural, biological, and clinical studies are beginning to unmask the role of HER3 signaling in human cancers, our understanding of this receptor is still in its infancy. Ongoing experimental studies and the arrival of HER3-targeting agents will provide much more insights into the relevance and functions of this receptor.
1. Guy PM, Platko JV, Cantley LC, Cerione RA, Carraway KL., 3rd Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci U S A. 1994;91:8132–6. [PubMed]
2. Sierke SL, Cheng K, Kim HH, Koland JG. Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein. Biochemical Journal. 1997;322:757–63. [PubMed]
3. Jura N, Shan Y, Cao X, Shaw DE, Kuriyan J. Structural analysis of the catalytically inactive kinase domain of the human HER3 receptor. Proc Nat Acad Sci USA. 2009 in press. [PubMed]
4. Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell. 2006;125:1137–49. [PubMed]
5. Zhang K, Sun J, Liu N, et al. Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2. J Biol Chem. 1996;271:3884–90. [PubMed]
6. Kani K, Warren CM, Kaddis CS, Loo JA, Landgraf R. Oligomers of ERBB3 Have Two Distinct Interfaces That Differ in Their Sensitivity to Disruption by Heregulin. 2005:8238–47. [PubMed]
7. Jura N, Endres NF, Engel K, et al. Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment. Cell. 2009;137:1293–307. [PMC free article] [PubMed]
8. Yoo JY, Wang XW, Rishi AK, et al. Interaction of the PA2G4 (EBP1) protein with ErbB-3 and regulation of this binding by heregulin. Br J Cancer. 2000;82:683–90. [PMC free article] [PubMed]
9. Soltoff SP, Carraway KL, 3rd, Prigent SA, Gullick WG, Cantley LC. ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol. 1994;14:3550–8. [PMC free article] [PubMed]
10. Prigent SA, Gullick WJ. Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J. 1994;13:2831–41. [PubMed]
11. Fedi P, Pierce JH, Di Fiore PP, Kraus MH. Efficient coupling with phosphatidylinositol 3-kinase, but not phospholipase C gamma or GTPase-activating protein, distinguishes ErbB-3 signaling from that of other ErbB/EGFR family members. Molecular and Cellular Biology. 1994;14:492–500. [PMC free article] [PubMed]
12. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86. [PubMed]
13. Sergina NV, Rausch M, Wang D, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437–41. [PMC free article] [PubMed]
14. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43. [PubMed]
15. Amler L, Makhija S, Januario T, et al. Downregulation of HER3 may predict clinical benefit in ovarian cancer from pertuzumab, a HER2 dimerization-inhibiting antibody; ASCO-NCI-EORTC Annual Meeting on Molecular Markers in Cancer; 2008. Abst #25.
16. Miller TW, Perez-Torres M, Narasanna A, et al. Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 2009;69:4192–201. [PMC free article] [PubMed]
17. Frogne T, Benjaminsen RV, Sonne-Hansen K, et al. Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat. 2009;114:263–75. [PMC free article] [PubMed]
18. Liu B, Ordonez-Ercan D, Fan Z, Edgerton SM, Yang X, Thor AD. Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. Int J Cancer. 2007;120:1874–82. [PubMed]
19. Osipo C, Meeke K, Cheng D, et al. Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer. Int J Oncol. 2007;30:509–20. [PubMed]
20. Erjala K, Sundvall M, Junttila TT, et al. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Clin Cancer Res. 2006;12:4103–11. [PubMed]
21. Zhang Y, Linn D, Liu Z, et al. EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance. Mol Cancer Ther. 2008;7:3176–86. [PMC free article] [PubMed]
22. Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoel MJ, et al. Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res. 2009;15:5445–56. [PubMed]
23. Cao Z, Wu X, Yen L, Sweeney C, Carraway KL., 3rd Neuregulin-induced ErbB3 downregulation is mediated by a protein stability cascade involving the E3 ubiquitin ligase Nrdp1. Mol Cell Biol. 2007;27:2180–8. [PMC free article] [PubMed]
24. Laederich MB, Funes-Duran M, Yen L, et al. The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J Biol Chem. 2004;279:47050–6. [PubMed]
25. Miller JK, Shattuck DL, Ingalla EQ, et al. Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer. Cancer Res. 2008;68:8286–94. [PMC free article] [PubMed]
26. Stutz MA, Shattuck DL, Laederich MB, Carraway KL, 3rd, Sweeney C. LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII. Oncogene. 2008;27:5741–52. [PMC free article] [PubMed]
27. Funes M, Miller JK, Lai C, Carraway KL, 3rd, Sweeney C. The mucin Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3. J Biol Chem. 2006;281:19310–9. [PubMed]
28. Iorio MV, Casalini P, Piovan C, et al. microRNA-205 regulates HER3 in human breast cancer. Cancer Res. 2009;69:2195–200. [PubMed]
29. Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J Biol Chem. 2007;282:1479–86. [PubMed]
30. Alimandi M, Romano A, Curia MC, et al. Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene. 1995;10:1813–21. [PubMed]
31. Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, 3rd, Hynes NE. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A. 2003;100:8933–8. [PubMed]
32. Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878–87. [PubMed]
33. Engelman JA, Janne PA, Mermel C, et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci U S A. 2005;102:3788–93. [PubMed]
34. Buac K, Xu M, Cronin J, Weeraratna AT, Hewitt SM, Pavan WJ. NRG1 / ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation. Pigment Cell Melanoma Res. 2009 [PMC free article] [PubMed]
35. Reschke M, Mihic-Probst D, van der Horst EH, et al. HER3 is a determinant for poor prognosis in melanoma. Clin Cancer Res. 2008;14:5188–97. [PubMed]
36. Ueno Y, Sakurai H, Tsunoda S, et al. Heregulin-induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells. Int J Cancer. 2008;123:340–7. [PubMed]
37. Potti A, Hille R, Koch M. Immunohistochemical determination of HER-2/neu in malignant melanoma. Anticancer Res. 2003;23:4067–9. [PubMed]
38. Sparrow LE, Heenan PJ. Differential expression of epidermal growth factor receptor in melanocytic tumours demonstrated by immunohistochemistry and mRNA in situ hybridization. Australas J Dermatol. 1999;40:19–24. [PubMed]
39. Prickett TD, Agrawal NS, Wei X, et al. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet. 2009;41:1127–32. [PMC free article] [PubMed]
40. Lee D, Yu M, Lee E, et al. Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium. J Clin Invest. 2009;119:2702–13. [PMC free article] [PubMed]
41. Tanner B, Hasenclever D, Stern K, et al. ErbB-3 predicts survival in ovarian cancer. J Clin Oncol. 2006;24:4317–23. [PubMed]
42. Schaefer KL, Brachwitz K, Braun Y, et al. Constitutive activation of neuregulin/ERBB3 signaling pathway in clear cell sarcoma of soft tissue. Neoplasia. 2006;8:613–22. [PMC free article] [PubMed]
43. Schaefer KL, Brachwitz K, Wai DH, et al. Expression profiling of t(12;22) positive clear cell sarcoma of soft tissue cell lines reveals characteristic up-regulation of potential new marker genes including ERBB3. Cancer Res. 2004;64:3395–405. [PubMed]
44. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127–37. [PubMed]
45. Cai Z, Zhang G, Zhou Z, et al. Differential binding patterns of monoclonal antibody 2C4 to the ErbB3-p185her2/neu and the EGFR-p185her2/neu complexes. Oncogene. 2008;27:3870–4. [PMC free article] [PubMed]
46. Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15:429–40. [PubMed]
47. Montero JC, Rodriguez-Barrueco R, Ocana A, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A. Neuregulins and cancer. Clin Cancer Res. 2008;14:3237–41. [PubMed]
48. Jones RB, Gordus A, Krall JA, MacBeath G. A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature. 2006;439:168–74. [PubMed]
49. Schulze WX, Deng L, Mann M. Phosphotyrosine interactome of the ErbB-receptor kinase family. Molecular Systems Biology. 2005 doi: 10.1038/msb4100012. [PMC free article] [PubMed]
50. Lemoine NR, Lobresco M, Leung H, et al. The erbB-3 gene in human pancreatic cancer. J Pathol. 1992;168:269–73. [PubMed]
51. Friess H, Yamanaka Y, Kobrin MS, Do DA, Buchler MW, Korc M. Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression. Clin Cancer Res. 1995;1:1413–20. [PubMed]
52. Ciardiello F, Kim N, Saeki T, et al. Differential expression of epidermal growth factor-related proteins in human colorectal tumors. Proc Natl Acad Sci U S A. 1991;88:7792–6. [PubMed]
53. Baiocchi G, Lopes A, Coudry RA, et al. ErbB family immunohistochemical expression in colorectal cancer patients with higher risk of recurrence after radical surgery. Int J Colorectal Dis. 2009;24:1059–68. [PubMed]
54. Kapitanovic S, Radosevic S, Slade N, et al. Expression of erbB-3 protein in colorectal adenocarcinoma: correlation with poor survival. J Cancer Res Clin Oncol. 2000;126:205–11. [PubMed]
55. Kountourakis P, Pavlakis K, Psyrri A, et al. Prognostic significance of HER3 and HER4 protein expression in colorectal adenocarcinomas. BMC Cancer. 2006;6:46. [PMC free article] [PubMed]
56. Maurer CA, Friess H, Kretschmann B, et al. Increased expression of erbB3 in colorectal cancer is associated with concomitant increase in the level of erbB2. Hum Pathol. 1998;29:771–7. [PubMed]
57. Lee JC, Wang ST, Chow NH, Yang HB. Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer. 2002;38:1065–71. [PubMed]
58. Rajkumar T, Gooden CS, Lemoine NR, Gullick WJ, Goden CS. Expression of the c-erbB-3 protein in gastrointestinal tract tumours determined by monoclonal antibody RTJ1. J Pathol. 1993;170:271–8. [PubMed]
59. Zhang XL, Yang YS, Xu DP, et al. Comparative Study on Overexpression of HER2/neu and HER3 in Gastric Cancer. World J Surg. 2009;33:2112–8. [PubMed]
60. Rickman OB, Vohra PK, Sanyal B, et al. Analysis of ErbB Receptors in Pulmonary Carcinoid Tumors. Clinical Cancer Research. 2009;15:3315–24. [PubMed]
61. Reinmuth N, Jauch A, Xu EC, et al. Correlation of EGFR mutations with chromosomal alterations and expression of EGFR, ErbB3 and VEGF in tumor samples of lung adenocarcinoma patients. Lung Cancer. 2008;62:193–201. [PubMed]
62. Fujimoto N, Wislez M, Zhang J, et al. High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res. 2005;65:11478–85. [PubMed]
63. Yi ES, Harclerode D, Gondo M, et al. High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas. Mod Pathol. 1997;10:142–8. [PubMed]
64. Witta SE, Dziadziuszko R, Yoshida K, et al. ErbB-3 expression is associated with E-cadherin and their coexpression restores response to gefitinib in non-small-cell lung cancer (NSCLC) Ann Oncol. 2009;20:689–95. [PMC free article] [PubMed]
65. Gordon-Thomson C, Jones J, Mason RS, Moore GP. ErbB receptors mediate both migratory and proliferative activities in human melanocytes and melanoma cells. Melanoma Res. 2005;15:21–8. [PubMed]
66. Simpson BJ, Phillips HA, Lessells AM, Langdon SP, Miller WR. c-erbB growth-factor-receptor proteins in ovarian tumours. Int J Cancer. 1995;64:202–6. [PubMed]
67. Leng J, Lang J, Shen K, Guo L. Overexpression of p53, EGFR, c-erbB2 and c-erbB3 in endometrioid carcinoma of the ovary. Chin Med Sci J. 1997;12:67–70. [PubMed]
68. Furger C, Fiddes RJ, Quinn DI, Bova RJ, Daly RJ, Sutherland RL. Granulosa cell tumors express erbB4 and are sensitive to the cytotoxic action of heregulin-beta2/PE40. Cancer Res. 1998;58:1773–8. [PubMed]
69. Campos S, Hamid O, Seiden MV, et al. Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer. J Clin Oncol. 2005;23:5597–604. [PubMed]
70. Lee CH, Huntsman DG, Cheang MC, et al. Assessment of Her-1, Her-2, And Her-3 expression and Her-2 amplification in advanced stage ovarian carcinoma. Int J Gynecol Pathol. 2005;24:147–52. [PubMed]
71. Steffensen KD, Waldstrom M, Andersen RF, et al. Protein levels and gene expressions of the epidermal growth factor receptors, HER1, HER2, HER3 and HER4 in benign and malignant ovarian tumors. Int J Oncol. 2008;33:195–204. [PubMed]
72. Koumakpayi IH, Diallo JS, Le PC, et al. Expression and nuclear localization of ErbB3 in prostate cancer. Clin Cancer Res. 2006;12:2730–7. [PubMed]
73. Koumakpayi IH, Diallo JS, Le Page C, et al. Low nuclear ErbB3 predicts biochemical recurrence in patients with prostate cancer. BJU Int. 2007;100:303–9. [PubMed]
74. Bobrow LG, Millis RR, Happerfield LC, Gullick WJ. c-erbB-3 protein expression in ductal carcinoma in situ of the breast. Eur J Cancer. 1997;33:1846–50. [PubMed]
75. Quinn CM, Ostrowski JL, Lane SA, Loney DP, Teasdale J, Benson FA. c-erbB-3 protein expression in human breast cancer: comparison with other tumour variables and survival. Histopathology. 1994;25:247–52. [PubMed]
76. Lemoine NR, Barnes DM, Hollywood DP, et al. Expression of the ERBB3 gene product in breast cancer. Br J Cancer. 1992;66:1116–21. [PMC free article] [PubMed]
77. Gasparini G, Gullick WJ, Maluta S, et al. c-erbB-3 and c-erbB-2 protein expression in node-negative breast carcinoma--an immunocytochemical study. Eur J Cancer. 1994;30A:16–22. [PubMed]
78. Koutras AK, Kalogeras KT, Dimopoulos MA, et al. Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. Br J Cancer. 2008;99:1775–85. [PMC free article] [PubMed]
79. Naidu R, Yadav M, Nair S, Kutty MK. Expression of c-erbB3 protein in primary breast carcinomas. Br J Cancer. 1998;78:1385–90. [PMC free article] [PubMed]
80. Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol. 2003;200:290–7. [PubMed]
81. Sassen A, Rochon J, Wild P, et al. Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients. Breast Cancer Research. 2008;10:13. [PMC free article] [PubMed]