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PubMed1995

Multiple essential functions of neuregulin in development.

Neuregulin (also called NDF, heregulin, GGF and ARIA) is a member of the EGF family which induces growth and differentiation of epithelial, glial and muscle cells in culture. The biological effects of the factor are mediated by tyrosine kinase receptors. Neuregulin can bind directly to erbB3 and erbB4 and receptor heterodimerization allows neuregulin-dependent activation of erbB2 (refs 1, 2, 5). A targeted mutation in mice reveals multiple essential roles of neuregulin in development. Here we show that neuregulin -/- embryos die during embryogenesis and display heart malformations. In addition, Schwann cell precursors and cranial ganglia fail to develop normally. The phenotype demonstrates that in vivo neuregulin acts locally and frequently in a paracrine manner. All cell types affected by the mutation express either erbB3 or erbB4, indicating that either of these tyrosine kinase receptors can be a component in recognition and transmission of essential neuregulin signals.

Animals↗

PubMed1995

Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor.

Various in vitro studies have suggested that ErbB4 (HER4) is a receptor for the neuregulins, a family of closely related proteins implicated as regulators of neural and muscle development, and of the differentiation and oncogenic transformation of mammary epithelia. Here we demonstrate that ErbB4 is an essential in vivo regulator of both cardiac muscle differentiation and axon guidance in the central nervous system (CNS). Mice lacking ErbB4 die during mid-embryogenesis from the aborted development of myocardial trabeculae in the heart ventricle. They also display striking alterations in innervation of the hindbrain in the CNS that are consistent with the restricted expression of the ErbB4 gene in rhombomeres 3 and 5. Similarities in the cardiac phenotype of ErbB4 and neuregulin gene mutants suggest that ErbB4 functions as a neuregulin receptor in the heart; however, differences in the hindbrain phenotypes of these mutants are consistent with the action of a new ErbB4 ligand in the CNS.

Animals↗

PubMed1995

Ligand-directed retroviral targeting of human breast cancer cells.

We explored the feasibility of designing retroviral vectors that can target human breast cancer cells with characteristic receptors via ligand-receptor interaction. The ecotropic Moloney murine leukemia virus envelope was modified by insertion of sequences encoding human heregulin. Ecotropic virus, which normally does not infect human cells, when pseudotyped with the modified envelope protein now crosses species to infect human breast cancer cell lines that overexpress HER-2 (human epidermal growth factor receptor; also called ERBB2) and HER-4 (also called ERBB4), while human breast cancer cell lines expressing low levels of these receptors remain resistant to infection. Since about 20% of human breast cancers overexpress HER-2 and some of breast cancer cell lines overexpress both HER-2 and HER-4, cell-specific targeting of retroviral vectors may provide a different approach for in vivo gene therapy of this type of breast cancer.

Breast Neoplasms↗

PubMed1995

HER4 expression correlates with cytotoxicity directed by a heregulin-toxin fusion protein.

We have constructed, expressed, and purified a fusion protein, HAR-TX beta 2, consisting of heregulin-beta 2 fused to a binding-defective form of Pseudomonas exotoxin A, PE40. The fusion protein was found to induce receptor tyrosine phosphorylation in CEM cells transfected with HER4 alone or in combination with HER2 but not in cells transfected with HER2 or HER1 alone. The phosphorylation of receptor tyrosines was both dose-dependent and saturable in amounts similar to those shown to be active for native heregulin. HAR-TX beta 2 was specifically cytotoxic toward a variety of carcinoma cell lines in the ng/ml range. However, some tumor cell lines were found to be insensitive to the cytotoxic action of the fusion protein even at > 2 micrograms/ml. Relative amounts of HER4, HER3, and HER2 were determined on seven cell lines sensitive and four cell lines insensitive to HAR-TX beta 2. All lines that express HER4 were killed by HAR-TX beta 2, while none lacking HER4 were affected. HAR-TX beta 2 was able to bind to and signal via tyrosine phosphorylation in cell lines that co-express HER2 and HER3 in the absence of HER4 without inducing cytotoxicity. Thus HAR-TX beta 2 may prove to be a useful reagent for the targeting and elimination of HER4-positive tumor cells.

ADP Ribose Transferases↗

PubMed1995

HER4 receptor activation and phosphorylation of Shc proteins by recombinant heregulin-Fc fusion proteins.

Heregulins (HRGs) are mosaic glycoproteins that bind to and induce the tyrosine phosphorylation of the HER4/p180erbB4 receptor. This work was aimed at studying the biological effects induced by recombinant epidermal growth factor (EGF)-like domains of HRGs as well as identifying intracellular molecules involved in HER4 signaling. To this end, we cloned the EGF-like domains of HRG-alpha, -beta 2, and -beta 3 into a eukaryotic expression vector in frame with sequences encoding a thrombin cleavage site followed by the Fc portion of a human IgG1. These chimeric genes directed the expression of recombinant fusion proteins, rHRGs-T-Fc, which specifically stimulated the phosphorylation of HER4/p180erbB4. We also show that rHRG-alpha-T-Fc bound to human breast cancer cells that express HER4 receptors and induced the expression of intercellular adhesion molecule-1. After thrombin protease cleavage of rHRGs-T-Fc, their EGF-like domains were purified and shown to stimulate protein phosphorylation in HER4-expressing cells. Moreover, the rHRG-beta 2 EGF-like domain markedly induced the phosphorylation of Shc proteins on tyrosine, suggesting a role for these adaptor molecules in HRG-mediated signaling.

Amino Acid Sequence↗

PubMed1995

Heregulin activation of extracellular acidification in mammary carcinoma cells is associated with expression of HER2 and HER3.

HER2, the erbB-2/neu proto-oncogene product, is a 185-kDa transmembrane glycoprotein related to the epidermal growth factor receptor. Overexpression of HER2 was reported in several human adenocarcinomas, including mammary and ovarian carcinomas. A family of glycoproteins, the heregulin/neu differentiation factors, was characterized and implicated as the ligands for HER2. Recently, it has been shown that HER2 alone is not sufficient to reconstitute high affinity heregulin receptors and that HER3 or HER4 may be the required components of the heregulin receptors on mammary carcinoma cells (Sliwkowski, M.X., Schaefer, G., Akita, R.W., Lofgren, J.A., Fitzpatrick, V.D., Nuijens, A., Fendly, B.M., Cerione, R.A., Vandlen, R.L., and Carraway, K.L., III (1994) J. Biol. Chem. 269, 14661-14665; Plowman, G.D., Green, J.M., Culouscou, J.-M., Carlton, G.W., Rothwell, V.M., and Buckley, W. (1993) Nature 366, 473-475). Using the Cytosensor to measure the extracellular acidification rate, we have examined the effects of recombinant human heregulin-alpha on three mammary carcinoma cell lines expressing HER2 (MDA-MB-453, SK-BR-3, and MCF-7), an ovarian carcinoma cell line expressing HER2 (SK-OV-3), and CHO-K1 and 293-EBNA cells stably transfected with HER2. By reverse transcription polymerase chain reaction and Western blotting, we found that the breast cells also express HER3 and that the ovarian line co-expresses the HER4 message. A dramatic increase in the acidification rate was observed for the mammary carcinoma cells co-expressing high levels of HER2 and HER3. In contrast, the ovarian cells expressing high levels of HER2 and low levels of HER4 or CHO-K1 and 293-EBNA cells expressing HER2 alone were not responsive to heregulin. When these same transfected cells were exposed to monoclonal anti-HER2 antibody followed by anti-IgG to cause aggregation of the HER2 molecules, an increase in the acidification rate was observed, indicating coupling of transfected HER2 to the signal transduction pathway. Transfection of HER2 into MCF-7 cells, on the other hand, gave 4-fold enhanced acidification responses. These data, together with the previously reported high affinity heregulin binding and activation of tyrosine phosphorylation in HER2 and HER3 co-transfected cells support the role of HER2 and HER3 as components of the heregulin receptor in breast cells.

Animals↗

PubMed1996

HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers.

The EGF receptor family of tyrosine kinase growth factor receptors is expressed in a variety of cell types and has been implicated in the progression of certain human adenocarcinomas. The most recent addition to this family of receptors, HER4, was expressed in NIH 3T3 cells to determine its biological and biochemical characteristics. Cells expressing HER4 were responsive to heregulin beta2 as demonstrated by an increase in HER4 tyrosine phosphorylation and ability to form foci on a cell monolayer. HER4 exhibited in vitro kinase activity and was able to phosphorylate the regulatory subunit of phosphatidylinositol 3-kinase and SHC. Peptide competition studies identified tyrosine 1056 of HER4 as the phosphatidylinositol 3-kinase binding site and tyrosines 1188 and 1242 as two potential SHC binding sites. Interestingly, transfection of HER4 into NIH 3T3 cells conferred responsiveness to EGF with respect to colony formation in soft agar. It was also found that in response to heregulin beta2, endogenous murine HER1 or transfected human HER1 became phosphorylated when HER4 was present. This demonstrates that HER1 and HER4 can exist in a heterodimer complex and likely activate each other by transphosphorylation.

3T3 Cells↗

PubMed2026

Association of ERBB4 and SHBG gene polymorphisms with polycystic ovarian syndrome in South Indian women: a case-control genetic analysis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a multifactorial endocrinological disorder with a substantial genetic component. However, the role of genes involved in follicular development and androgen regulation remains incompletely understood, particularly in South Indian populations. This study aimed to evaluate how variations in the ERBB4 and SHBG genes affect PCOS risk. METHODOLOGY: A hospital-based case-control study was conducted among 400 South Indian women, comprising 200 women with PCOS and 200 age-matched healthy controls. Genomic DNA was extracted to study SNPs at ERBB4 (rs2178575 and rs1351592) and SHBG (rs1799941 and rs727428) using ARMS-PCR genotyping. The study compared genotype and allele frequencies between cases and controls while assessing their associations with allelic, homozygous, heterozygous, dominant, recessive, and over-dominant genetic models. Genotyping accuracy was confirmed by re-genotyping and Sanger sequencing of a subset of samples. RESULTS: The ERBB4 rs2178575 polymorphism demonstrated a significant association with PCOS, as the AA genotype and A allele combination increased risk across all three genetic models, including homozygous, recessive, and allelic models. The ERBB4 rs1351592 variant was associated with 3-fold higher risk of PCOS in heterozygous and GC carriers. The SHBG rs1799941 polymorphism showed a significant link to PCOS through its effects on heterozygous and allelic states, whereas rs727428 displayed no significant connection due to its monomorphic distribution. CONCLUSION: These findings suggest that polymorphisms in ERBB4 and SHBG may contribute to PCOS susceptibility in South Indian women in a locus- and model-specific manner, revealing the intricate genetic structure that defines this medical condition.

Humans↗

PubMed1995

Localization of the human HER4/erbB-4 gene to chromosome 2.

The HER4/erbB-4 gene has been isolated as the fourth member of the human EGFR subfamily of tyrosine kinases and has been reported to encode a receptor for NDF/heregulin. In the present study we determined the chromosomal location of the HER4/erbB-4 gene within the human genome. Using human cDNA probes in fluorescence in situ hybridization (FISH), we mapped the HER4/erbB-4 gene to human chromosome 2q33.3-34. This finding established that also the HER4/erbB-4 gene is located in close vicinity of homeobox and collagen gene loci, as is the case for the related EGFR, erbB-2/neu and erbB-3. Aberrations of this chromosomal region associated with T cell leukemias and lymphomas as well as alveolar rhabdomyosarcomas raise the possibility that HER4/erbB-4 might be activated in these tumour types.

Chromosome Mapping↗

PubMed1995

The influence of heregulins on human Schwann cell proliferation.

The use of Schwann cell (SC) autotransplantation to influence neural repair in humans is dependent upon identifying mitogens that will effectively expand human Schwann cells (SCs) in culture. The recent purification and molecular cloning of glial growth factor (GGF), a potent mitogen for rat Schwann cells, has led to the recognition that a family of proteins (GGF/HRG/NDF/ARIA) are alternatively spliced products of a single gene. The heregulins (HRGs) have been characterized with respect to their influence on human breast cancer cell lines; here we examined whether the HRGs have mitogenic activity for human SCs. Using DNA synthesis assays and serial passaging of cells in culture, we demonstrate that HRG is an effective mitogen for human SCs and that, in the presence of agents that elevate cAMP, it is possible to expand these cells over multiple passages without overwhelming fibroblast contamination. One putative target for this family of proteins is p185erbB2, and EGF-like receptor tyrosine kinase that is encoded by the erbB2 protooncogene. In this report we also demonstrate that the erbB2/3/4 messages as well as the erbB2/3 receptor proteins are present within cultured human SCs. The addition of HRG to human SCs results in tyrosine phosphorylation of a 185 kDa protein. In the presence of stimulatory concentrations of HRG, a blocking monoclonal antibody (2C4) to p185erbB2 is capable of significantly inhibiting phosphorylation of a 185 kDa protein as well as the subsequent incorporation of 3H-thymidine within the human SC. These latter results implicate an important role for p185erbB2 in mediating the mitogenic response of human SCs to HRGs.

Adenylyl Cyclases↗

PubMed1996

ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer.

Overexpression of the erbB-2 gene contributes to aggressive behavior of various human adenocarcinomas, including breast cancer, through an unknown molecular mechanism. The erbB-2-encoded protein is a member of the ErbB family of growth factor receptors, but no direct ligand of ErbB-2 has been reported. We show that in various cells ErbB-2 can form heterodimers with both EGF receptor (ErbB-1) and NDF receptors (ErbB-3 and ErbB-4), suggesting that it may affect the action of heterologous ligands without the involvement of a direct ErbB-2 ligand. This possibility was addressed in breast cancer cells through either overexpression of ErbB-2 or by blocking its delivery to the cell surface by means of an endoplasmic reticulum-trapped antibody. We report that ErbB-2 overexpression enhanced binding affinities to both EGF and NDF, through deceleration of ligand dissociation rates. Likewise, removal of ErbB-2 from the cell surface almost completely abolished ligand binding by accelerating dissociation of both growth factors. The kinetic effects resulted in enhancement and prolongation of the stimulation of two major cytoplasmic signaling pathways, namely: MAP kinase (ERK) and c-Jun kinase (SAPK), by either ligand. Our results imply that ErbB-2 is a pan-ErbB subunit of the high affinity heterodimeric receptors for NDF and EGF. Therefore, the oncogenic action of ErbB-2 in human cancers may be due to its ability to potentiate in trans growth factor signaling.

Adenocarcinoma↗

PubMed1996

Signal transduction pathways induced by heregulin in MDA-MB-453 breast cancer cells.

Heregulins (HRGs) induce tyrosine phosphorylation of several members of the erb-B family of receptors. Although originally isolated as the ligands for p185c-erb-2, recent evidence suggests that other receptors of the erbB family, including p180erbB-3 and p180erbB-4, are their true cognate receptors. Stimulation of MDA MB-453 cells with HRG beta 2 resulted in the tyrosine phosphorylation of p185c-erbB-2 and p180erbB-4 in a time- and dose-dependent fashion. This event was accompanied by the formation of multimeric complexes between the activated receptors and SH2-containing proteins. Ligand caused p120-rasGTPase activating protein (GAP), SHC and the p85 subunit of phosphatidylinositol-3'-kinase (PI3K) to be associated with both p185c-erbB-2 and p180erbB-4. In addition, tyrosine phosphorylation of p85-PI3K and SHC, but not of GAP or of its associated p62 and p190 proteins, was also detected. HRG also induced the association of GRB2 with tyrosine phosphorylated p185c-erbB-2, p180erbB-4 and SHC. Activation of mitogen-activated protein kinase (MAPK) ( > 30-fold over untreated controls) was observed upon receptor(s) activation, as it was the induction of the immediate early gene c-fos ( > 200-fold). These observations suggest that p21ras activation plays a role in the HRG pathway. Furthermore, comparative analysis of the binding of p85-PI3K to 185c-erbB-2 and p180erbB-4, revealed a preferential association with activated p180erbB-4. These findings might suggest a model of HRG action in which the relative expression of the various erb-B family members and the partitioning of signal transduction molecules between each type of receptor might determine the nature of the signal elicited by the ligand and the biological response attained.

1-Phosphatidylinositol 4-Kinase↗

PubMed1996

Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2.

Members of the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases have been implicated in the pathogenesis of various malignancies. The ability of one EGFR subfamily member to influence, or function synergistically with, another is likely to be a general feature of these receptors. To assess the role of receptor heterodimerization, we analyzed the ability of Neu differentiation factor (NDF) to induce cell growth and transformation of NIH 3T3 cells transfected with different combinations of the EGFR subfamily of receptors. NDF induced mitogenesis, but not transformation, of cells expressing either HER3 or HER4 alone. However, NDF-induced cell transformation was observed when either HER1 or HER2 was coexpressed with HER3 or HER4. In analogous receptor phosphorylation experiments, NDF-induced transphosphorylation appears to be correlated with synergistic transformation of NIH 3T3 cells. Interestingly, transphosphorylation between HER1 and HER4 can be stimulated by either EGF or NDF.

3T3 Cells↗

PubMed1994

ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms.

Neu differentiation factor (NDF or heregulin) elevates tyrosine phosphorylation of the ErbB-2 receptor tyrosine kinase, and it was, therefore, thought to function as a ligand of this receptor. However, several lines of evidence raised the possibility that the interaction between NDF and ErbB-2 involves another molecule, which belongs to the family of epidermal growth factor receptors. To address this question we constructed soluble chimeric proteins between alkaline phosphatase and the extracellular domains of ErbB-2 and either ErbB-3 or ErbB-4, two newly recognized members of the epidermal growth factor receptor family. Using the soluble proteins we found that beta isoforms of NDF specifically bind to the ErbB-3 and ErbB-4 receptors but not to the soluble ErbB-2 protein. When ectopically expressed in monkey fibroblasts, the full-length ErbB-3 and ErbB-4 receptors conferred specific binding to NDF. In these cells ErbB-3 displayed lower ligand binding affinity than ErbB-4, but like the latter receptor it preferred to bind the beta isoform over the alpha class of NDFs. These results indicate that both ErbB-3 and ErbB-4 function as physiological receptors of all NDF isoforms and suggest that a still unknown ligand of ErbB-2 exists.

Amino Acid Sequence↗

PubMed1996

All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired.

Four transmembrane tyrosine kinases constitute the ErbB receptor family: the epidermal growth factor (EGF) receptor, ErbB-2, ErbB-3, and ErbB-4. We have measured the endocytic capacities of all four members of the EGF receptor family, including ErbB-3 and ErbB-4, which have not been described previously. EGF-responsive chimeric receptors containing the EGF receptor extracellular domain and different ErbB cytoplasmic domains (EGFR/ErbB) have been employed. The capacity of these growth factor-receptor complexes to mediate 125I-EGF internalization, receptor down-regulation, receptor degradation, and receptor co-immunoprecipitation with AP-2 was assayed. In contrast to the EGF receptor, all EGFR/ErbB receptors show impaired ligand-induced rapid internalization, down-regulation, degradation, and AP-2 association. Also, we have analyzed the heregulin-responsive wild-type ErbB-4 receptor, which does not mediate the rapid internalization of 125I-heregulin, demonstrates no heregulin-regulated receptor degradation, and fails to form association complexes with AP-2. Despite the substantial differences in ligand-induced receptor trafficking between the EGF and ErbB-4 receptors, EGF and heregulin have equivalent capacities to stimulate DNA synthesis in quiescent cells. These results show that the ligand-dependent down-regulation mechanism of the EGF receptor, surprisingly, is not a property of any other known ErbB receptor family member. Since endocytosis is thought to be an attenuation mechanism for growth factor-receptor complexes, these data imply that substantial differences in attenuation mechanisms exist within one family of structurally related receptors.

3T3 Cells↗

PubMed1996

An immunological approach reveals biological differences between the two NDF/heregulin receptors, ErbB-3 and ErbB-4.

The group of subtype I transmembrane tyrosine kinases includes the epidermal growth factor (EGF) receptor (ErbB-1), an orphan receptor (ErbB-2), and two receptors for the Neu differentiation factor (NDF/heregulin), namely: ErbB-3 and ErbB-4. Here we addressed the distinct functions of the two NDF receptors by using an immunological approach. Two sets of monoclonal antibodies (mAbs) to ErbB-3 and ErbB-4 were generated through immunization with recombinant ectodomains of the corresponding receptors that were fused to immunoglobulin. We found that the shared ligand binds to highly immunogenic, but immunologically distinct sites of ErbB-3 and ErbB-4. NDF receptors differed also in their kinase activities; whereas the catalytic activity of ErbB-4 was activable by mAbs, ErbB-3 underwent no activation by mAbs in living cells. Likewise, down-regulation of ErbB-4, but not ErbB-3, was induced by certain mAbs. By using the generated mAbs, we found that the major NDF receptor on mammary epithelial cells is a heterodimer of ErbB-3 with ErbB-2, whereas an ErbB-1/ErbB-2 heterodimer, or an ErbB-1 homodimer, is the predominant species that binds EGF. Consistent with ErbB-2 being a shared receptor subunit, its tyrosine phosphorylation was increased by both heterologous ligands and it mediated a trans-inhibitory effect of NDF on EGF binding. Last, we show that the effect of NDF on differentiation of breast tumor cells can be mimicked by anti-ErbB-4 antibodies, but not by mAbs to ErbB-3. Nevertheless, an ErbB-3-specific mAb partially inhibited the effect of NDF on cellular differentiation. These results suggest that homodimers of ErbB-4 are biologically active, but heterodimerization of the kinase-defective ErbB-3, probably with ErbB-2, is essential for transmission of NDF signals through ErbB-3.

Animals↗

PubMed1995

Hyperactive autocrine loop mediated by a NDF-related factor in neoplastic hamster embryo fibroblasts expressing an activated cph oncogene.

We described previously the characterization of a novel oncogene, cph, activated in primary Syrian hamster embryo fibroblasts by exposure to 3-methylcholanthrene (Velasco et al., Oncogene 9:2065-2069, 1994). The present report describes the participation in the neoplastic conversion of cph-expressing (81C39) hamster fibroblasts of a hyperactive autocrine loop involving a neu differentiation factor [NDF]-like protein. The tyrosine phosphorylation of the p185erbB-2 receptor in the human breast carcinoma MDA-MB-453 cells was stimulated by conditioned medium from neoplastic 81C39 cells. The extent of this stimulatory effect was much greater than that induced by conditioned medium from normal 84-3 hamster cells. The p185erbB-2 tyrosine phosphorylation-stimulating activity was partially blocked by the heparin analogue pentosan polysulfate [PPS], a known antagonist of p185erbB-2 ligands, and was partially purified from 81C39 conditioned medium by heparin-Sepharose chromatography. The level of p185erbB-2 tyrosine phosphorylation-stimulating activity in the heparin-Sepharose fractions correlated directly with their content in NDF-like protein as immunodetected with an anti-rat NDF antibody. Consistently, the steady-state level of NDF-related mRNA was found to be four times greater in neoplastic 81C39 cells than in normal 84-3 cells. However, the levels of erbB-2 mRNA were similar in both cell types, while the expression of erbB-4 mRNA was upregulated in the neoplastic fibroblasts. The ability of 81C39 conditioned medium to stimulate protein tyrosine phosphorylation and to induce other PPS-sensitive growth responses on 81C39 cells themselves suggested the involvement of an autocrine loop in their neoplastic conversion. The participation of a NDF-related factor in this autocrine loop was confirmed by the ability of an anti-NDF antibody to block the mitogenic activity present in their own conditioned medium. The involvement of the cph oncogene in the upregulation of NDF-related expression was evidenced when cph-transformed NIH3T3 fibroblasts showed elevated levels of NDF-related mRNA, and their conditioned medium induced tyrosine phosphorylation on MDA-MB-453 cells, reproducing the effect of the medium from 81C39 hamster cells.

3T3 Cells↗

PubMed1995

Interaction between erbB-receptors and heregulin in breast cancer tumor progression and drug resistance.

The type I growth factor receptor family is increasingly recognized as important in the development and maintenance of breast cancer. The family currently consists of four closely related members: the epidermal growth factor receptor (EGF-R/erbB-1), erbB-2, erbB-3 and erbB-4. Putative ligands which bind directly to or indirectly activate erbB-2/3/4 have been characterized recently. This still growing family of EGF-related growth factors includes gp30, its homolog heregulin (HRG), the rat homolog neu differentiation factor (NDF), glial growth factors (GLIA), ARIA and a 50 kDa factor from COLO 16 cells. The understanding of the function, biology and interactions of these growth factor receptors and their ligands will have far-reaching implications for the prognosis and treatment of breast cancer. This review focuses on advances and future directions for further investigations intended to clarify the mechanism and significance of erbB/ligand interactions in breast cancer.

Animals↗