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Query: UNIPROT:P06889 (Mol)
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The high incidence of human epidermal growth factor receptor (HER)2 overexpression on breast and various other cancer cells and the prognostic and potentially predictive value of HER2 render this growth receptor a novel and important therapeutic target. Out of a wide range of assays that have been used in research for the detection of HER2 status, only two techniques are now predominant and readily applicable in the routine clinical pathology laboratory: determination of HER2 overexpression by immunohistochemistry (IHC) and HER2 gene amplification by fluorescence in situ hybridisation (FISH). In a retrospective study on a cohort of 173 archival invasive breast carcinomas a chromogenic in situ hybridisation (CISH) assay for the detection of HER2 amplification was established. Results were compared to HercepTest, which is the most frequently used method for detecting HER2 alteration. Additionally, HER2 gene copy number was investigated using differential PCR (dPCR) as a testing system. Discrepant cases between CISH and HercepTest and all IHC positive cases (2 + and 3 +), a total of 42 cases, were analysed with FISH Path Vysion(Vysis) assay. HER2 overexpression was found by IHC in 24.3%, HER2 amplification by CISH in 19.1% and by dPCR in 9.2% of the tumours. The overall concordance rate between CISH and IHC was 95.9%, between dPCR and IHC 85% and between CISH and FISH 100%, respectively. Among 25 HercepTest positive cases (score 3+) two showed no gene amplification and four out of 13 tumours with score 2 + were negative with CISH and FISH. The current study showed that CISH offers an ideal approach that allows detection of HER2 amplification in the context of morphology, whereas the major drawback of dPCR is the impracticability of tissue differentiation of invasive and non-invasive carcinoma.
J Mol Histol 2004 Aug
PMID:Comparison of chromogenic in situ hybridization with other methodologies for HER2 status assessment in breast cancer. 1561 19

Clinical resistance to the HER-2 oncogene-targeting drug trastuzumab (Herceptin) exists, but studies of the resistance mechanisms are hampered by the lack of suitable experimental model systems. We established a carcinoma cell line (designated JIMT-1) from a pleural metastasis of a 62-year old patient with breast cancer who was clinically resistant to trastuzumab. JIMT-1 cells grow as an adherent monolayer and form xenograft tumors in nude mice. JIMT-1 cells have an amplified HER-2 oncogene, which showed no identifiable mutations in its coding sequence. JIMT-1 cells overexpress HER-2 mRNA and protein, and the levels of HER-1, HER-3, and HER-4 mRNA and protein were similar to the trastuzumab-sensitive cell line SKBR-3. The cell line lacks expression of hormone receptors (estrogen receptors and progesterone receptors) and is phenotypically of epithelial progenitor cell origin, as evidenced by immunohistochemical positivity for both cytokeratins 5/14 and 8/18. JIMT-1 cells were insensitive to trastuzumab and another HER-2-inhibiting drug, pertuzumab (2C4), in vitro and in xenograft tumors. Small molecule tyrosine kinase inhibitors Ci1033 and ZD1839 inhibited the JIMT-1 cell growth but to a lesser degree than in trastuzumab-sensitive BT-474 cells. The lack of growth inhibition was rationalized by the unaltered Akt phosphorylation in JIMT-1 cells. Erk1/2 phosphorylation was slightly reduced but still evident in JIMT-1 cells. We conclude that the JIMT-1 cell line provides a valuable experimental model for studies of new trastuzumab-resistance mechanisms.
Mol Cancer Ther 2004 Dec
PMID:Characterization of a novel cell line established from a patient with Herceptin-resistant breast cancer. 1602 Jun 72

Genistein is a major component of soybean isoflavone and has preventive effect against breast cancer. In breast cancer, the over-expression of HER-2 contributes to malignant transformation of the cancer cells. The present study was undertaken to estimate if genistein could act as a useful anti-cancer agent against a breast cancer cell overexpressing HER-2 in combination with a conventional chemotherapy agent, adriamycin (ADR). Genistein enhanced cytotoxic effect of ADR at low doses less than IC50 against the human breast cancer cell. The enhancing effect was mainly dependent on the elevation of necrotic-like cell death but not apoptotic cell death. In conjugation with this event, remarkable inactivation of HER-2 and Akt in the breast cancer cell was caused by the combination of genistein and ADR. These results suggest that genistein enhances necrotic-like cell death of the breast cancer cells through the inactivation of HER-2 receptor and Akt in combination with ADR.
Res Commun Mol Pathol Pharmacol 2003
PMID:Genistein, a soy isoflavone, enhances necrotic-like cell death in a breast cancer cell treated with a chemotherapeutic agent. 1568 14

Persistent activation of T-lymphocytes requires two signals: one is initiated by T-cell receptor binding to antigenic peptide presented by MHC molecules. In addition, binding of the B7 family members CD80 or CD86 on professional antigen presenting cells to CD28 on T cells is considered to provide an important costimulatory signal. Activation without costimulation induces T-cell unresponsiveness or anergy. To selectively localize costimulatory activity to the surface of tumor cells and enhance activation of tumor-specific T cells, we have developed a novel molecular design for bispecific costimulatory proteins with antibody-like structure. Within a single polypeptide chain we have assembled the IgV-like, CD28-binding domain of human CD86 (CD86(111)) together with hinge, CH2 and CH3 domains of human IgG1, and the scFv(FRP5) antibody fragment which recognizes the ErbB2 (HER2) protooncogene present at high levels on the surface of many human tumor cells. Upon expression in the yeast Pichia pastoris, the resulting CD86(111)-IgG-scFv(FRP5) protein could be purified as a homodimeric, tetravalent molecule from culture supernatants using single-step affinity chromatography. Bispecific binding of the molecule to ErbB2 on the surface of tumor cells and to the B7 counter receptor CTLA-4 was demonstrated by FACS analysis. Potent costimulatory activity of chimeric CD86(111)-IgG-scFv(FRP5) was confirmed by its ability to stimulate the proliferation of primary human lymphocytes pre-activated by low concentrations of anti-CD3 antibody. Our results suggest that such multivalent soluble proteins which combine specific targeting to tumor cells with costimulatory activity may become useful tools to elicit and/or improve T-cell mediated, tumor-specific immune responses.
J Mol Biol 2005 Mar 11
PMID:A novel bispecific tetravalent antibody fusion protein to target costimulatory activity for T-cell activation to tumor cells overexpressing ErbB2/HER2. 1571 82

The protein product of the HER2 oncogene is overexpressed in an estimated 25 to 30% of breast carcinomas and is considered an indicator of poor clinical outcome. The bcl-2 and the bcl-x-L genes are the 2 main genes of the bcl-2 gene family that suppress tumor cell death/apoptosis. HER2 gene amplification is also described in a percentage of cases of ductal carcinoma in situ (DCIS) of the breast. However, the relationship of such overexpression with the apoptosis-suppressing genes is currently unknown. A total of 37 consecutive cases of DCIS were immunostained for HER2 overexpression (clone CB11, Ventana), and expression of bcl-2 and bcl-x-L. DCIS cases were graded using the criteria of Holland et al. HER2 overexpression was scored 0 to 3+; 0 and 1+ were considered negative staining and 2+ and 3+ were considered positive staining. HER2 gene amplification was also confirmed with fluorescent in situ hybridization (FISH). HER2 was positive in 22 of the 37 DCIS cases (60%) in accordance with previous reports. Immunohistochemical overexpression of HER2 was also highly correlated with HER2 amplification by FISH. HER2 overexpression (confirmed by FISH) was mostly seen in grade II (9 of 17) and grade III (9 of 12) DCIS lesions. Only 1 of the HER2-amplified cases was a grade I lesion. Furthermore, HER2 overexpression correlated with the presence of necrosis (P=0.003). Similarly, of the cases overexpressing HER2 at the highest level (3+), 90% were grade II or grade III lesions. A total of 73% of these cases also exhibited necrosis. Overexpression of HER2 3+ was also highly correlated with the presence of the apoptosis-suppressing gene bcl-x-L (coexpression in 87% of cases, P=0.01) but not with the prototype apoptosis-suppressing gene bcl-2 (coexpression in 50% of cases, P value not significant). First, in DCIS overexpression of HER2 the majority of grade II and grade III lesions is seen, and this correlates with the presence of necrosis. Second, HER2 overexpression is also highly correlated with the expression of the apoptosis-suppressing gene bcl-x-L, but not with the prototype apoptosis-suppressing gene bcl-2. These differences may prove useful in defining groups of DCIS lesions with enhanced tumor cell growth and propensity for progression to invasion.
Appl Immunohistochem Mol Morphol 2005 Mar
PMID:Correlation of HER2 gene amplification with expression of the apoptosis-suppressing genes bcl-2 and bcl-x-L in ductal carcinoma in situ of the breast. 1572 88

Inactivation of epidermal growth factor receptor (EGFR) family members represents a promising strategy for the development of selective therapies against epithelial cancers. Current anti-EGFR therapies, such as cetuximab (Erbitux), gefitinib (Iressa), or trastuzumab (Herceptin), target EGFR or HER-2 but not both. Because solid tumors express different EGFRs, identification of inhibitor(s), targeting multiple EGFR family members may provide a therapeutic benefit to a broader patient population. We have identified a natural inhibitor of EGFRs called EGFR-related protein (ERRP), a 53 to 55 kDa protein that is present in most, if not all, normal human epithelial cells. The growth of colon (HCT-116, Caco2, and HT-29) and breast (MDA-MB-468 and SKBR-3) cancer cells expressing varying levels of EGFR, HER-2, and/or HER-4 was inhibited by recombinant ERRP in a dose-dependent manner. In contrast, ERRP caused no inhibition of growth of normal mouse fibroblast cell lines (NIH-3T3, NIH-3T3/P67), and the growth of nontransformed rat small intestinal IEC-6 cells expressing relatively low levels of EGFRs was inhibited only at high doses of ERRP. Transforming growth factor-alpha or heparin-binding epidermal growth factor-induced activation of EGFR and HER-2 was inhibited by ERRP in colon and breast cancer cells expressing high levels of EGFR or HER-2. In contrast, cetuximab inhibited the growth- and ligand-induced activation of EGFR in cell lines expressing high levels of EGFR, whereas trastuzumab was effective only in HER-2-overexpressing cells. ERRP and trastuzumab, but not cetuximab, attenuated heregulin-alpha-induced activation of colon and breast cancer cells that expressed high levels of HER-2. Furthermore, ERRP, but not cetuximab or trastuzumab, significantly induced apoptosis of colon and breast cancer cells. None of these agents induced apoptosis of either NIH-3T3 mouse fibroblast or normal rat small intestinal IEC cells. Our results suggest that ERRP is an effective pan-erbB inhibitor and, thus, may be a potential therapeutic agent for a wide variety of epithelial cancers expressing different levels and subclasses of EGFRs.
Mol Cancer Ther 2005 Mar
PMID:Epidermal growth factor receptor (EGFR)-related protein inhibits multiple members of the EGFR family in colon and breast cancer cells. 1712 43

Currently, the standard of care for estrogen receptor (ER)-positive breast cancer is 5 years of tamoxifen (TAM) or an aromatase inhibitor (AI) such as anastrozole. New studies indicate that extending antiestrogen therapy beyond 5 years with sequential regimens will improve disease-free survival. Based on the emerging concept that longer therapies are better, we have developed sequential models of tamoxifen-resistant breast cancer in vivo to mimic the clinical scenario of long-term antiestrogen therapy. The goal of the current study was to investigate the consequences of long-term treatment with tamoxifen on the growth of breast tumors in athymic mice. The results demonstrate that there are distinct phases of resistance to tamoxifen that correlate with time of treatment and expression of HER2/neu mRNA. In the treatment phase, 17beta-estradiol (E2) stimulated growth, while TAM inhibited growth of MCF-7 tumors (MCF-7E2). The withdrawal of treatment, mimicking the use of an AI, completely prevented growth. In Phase I resistance, the tumors (MCF-7TAMST) were growth-stimulated by either E2 or TAM, but inhibited by no treatment, fulvestrant, or E2 + fulvestrant. Phase II-resistant tumors (MCF-7TAMLT) were treated for more than 5 years and growth-stimulated by TAM. However, no treatment, fulvestrant, or E2 completely inhibited growth. Interestingly, the few tumors (MCF-7TAMLT) that survived in response to E2 were robustly re-stimulated by E2 after transplantation into new generations of athymic mice. These E2-stimulated tumors (MCF-7TAME) were inhibited by TAM in a dose-dependent similar to their parental tumors (MCF-7E2). In addition, the MCF-7TAME tumors were inhibited by either no treatment or fulvestrant. HER2/neu and HER3 mRNAs were over-expressed in TAM-stimulated MCF-7TAMLT tumors and remained high in E2-stimulated MCF-7TAME tumors. The data indicate that complete reversal of resistance to TAM can be achieved with the use of low dose E2 therapy. Also, these data suggest that over-expression of HER2/neu alone is insufficient to predict resistance to TAM. Based on the results, we suggest using an alternating treatment regimen, cycling antiestrogen with estrogen therapy to avoid drug-resistance.
J Steroid Biochem Mol Biol 2005 Feb
PMID:Reversal of tamoxifen resistant breast cancer by low dose estrogen therapy. 1586 Feb 67

An accurate and reproducible assay method for determining HER2 status is crucial, as a positive HER2 gene status is an eligibility requirement for Herceptintrade mark therapy. Although immunohistochemical (IHC) assessment is both practical and inexpensive, a worrying trend of high false-positive rates has been reported. Fluorescence in situ hybridization (FISH) is the universally accepted gold standard for confirming IHC 2+ cases and ambiguous results but is costly and requires specialized equipment and technical expertise. Chromogenic in situ hybridization (CISH) amalgamates the practical advantages of IHC with the reproducibility of FISH, and high concordance between the CISH and FISH methods has been reported in conventional sections. Tissue microarrays (TMAs) allow high throughput of specimens, and HER2 status assessment in TMA cores using IHC and FISH has correlated well with scores in conventional sections. The authors used TMA technology to compare the efficacy of ZYMED(R) CISH with PathVysiontrade mark FISH in a cohort of 119 archival breast resection cases and investigated possible intratumoral heterogeneity in a "mini-array" of 21 HercepTest "equivocal"/2+ cases. Concordance between FISH and CISH in TMA sections was 99%. All prescored 2+ HercepTest cases were nonamplified. Four 3+ HercepTest cases were classed as potential false-positives. The authors suggest that confirmatory ISH should be performed on all positive HercepTest cases. CISH was easier to perform and quicker to enumerate than FISH. The authors conclude that CISH is a practical alternative to FISH as a confirmatory tool for HER2 gene amplification status. Intratumoral heterogeneity did not affect the patient's HER2 status.
Appl Immunohistochem Mol Morphol 2005 Jun
PMID:HER2 positivity in breast carcinoma: a comparison of chromogenic in situ hybridization with fluorescence in situ hybridization in tissue microarrays, with targeted evaluation of intratumoral heterogeneity by in situ hybridization. 1589 35

Transforming growth factor beta (TGF-beta) inhibits proliferation and promotes cell migration. In TGF-beta-treated MCF10A mammary epithelial cells overexpressing HER2 and by chromatin immunoprecipitation, we identified novel Smad targets including protein tyrosine phosphatase receptor type kappa (PTPRK). TGF-beta up-regulated PTPRK mRNA and RPTPkappa (receptor type protein tyrosine phosphatase kappa, the protein product encoded by the PTPRK gene) protein in tumor and nontumor mammary cells; HER2 overexpression down-regulated its expression. RNA interference (RNAi) of PTPRK accelerated cell cycle progression, enhanced response to epidermal growth factor (EGF), and abrogated TGF-beta-mediated antimitogenesis. Endogenous RPTPkappa associated with EGF receptor and HER2, resulting in suppression of basal and ErbB ligand-induced proliferation and receptor phosphorylation. In MCF10A/HER2 cells, TGF-beta enhanced cell motility, FAK phosphorylation, F-actin assembly, and focal adhesion formation and inhibited RhoA activity. These responses were abolished when RPTPkappa was eliminated by RNA interference (RNAi). In cells expressing RPTPkappa RNAi, phosphorylation of Src at Tyr527 was increased and (activating) phosphorylation of Src at Tyr416 was reduced. These data suggest that (i) RPTPkappa positively regulates Src; (ii) HER2 signaling and TGF-beta-induced RPTPkappa converge at Src, providing an adequate input for activation of FAK and increased cell motility and adhesion; and (iii) RPTPkappa is required for both the antiproliferative and the promigratory effects of TGF-beta.
Mol Cell Biol 2005 Jun
PMID:Transforming growth factor {beta} (TGF-{beta})-Smad target gene protein tyrosine phosphatase receptor type kappa is required for TGF-{beta} function. 1589 72

HER2/neu, a transmembrane glycoprotein overexpressed in several types of human cancers, is a potential target for active immunotherapy. However, this protein and especially its extracellular domain (ECD(HER2)), is weakly immunogenic and is poorly processed by dendritic cells (DCs). Previously, we showed that anti-HER2/neu IgG3-(IL-2) and anti-HER2/neu IgG3-(GM-CSF) fusion proteins can enhance the immunogenicity of ECD(HER2) in mice, and that the non-covalent physical association between each antibody fusion proteins and ECD(HER2) was critical to elicit optimal protective immunity against HER2/neu expressing tumors. We now use the professional antigen-presenting DCs to investigate the effect of the antibody fusion protein binding to ECD(HER2) on its trafficking and presentation. We found that when the extracellular domain of HER2/neu fused to ovalbumin (OVA-ECD(HER2)) is bound by HER2/neu-specific antibody-(IL-2) or antibody-(GM-CSF) fusion proteins, the bound antigen is more efficiently processed by murine bone-marrow-derived dendritic cells (BMDCs) and presented to OVA-specific T-cells than the unbound OVA-ECD(HER2). We also found that ECD(HER2) bound by anti-HER2/neu IgG3-(IL-2) is very efficiently internalized and that the internalized ECD(HER2) is not retained in the early endosomal compartments but traffics to the antigen-processing compartments. These results are consistent with our earlier in vivo studies and suggest that both antibody-(IL-2) and antibody-(GM-CSF) fusion proteins can be used to enhance the immune response to poorly immunogenic antigens including tumor-associated antigens (TAAs).
Mol Immunol 2006 Feb
PMID:Anti-HER2/neu IgG3-(IL-2) and anti-HER2/neu IgG3-(GM-CSF) promote HER2/neu processing and presentation by dendritic cells: implications in immunotherapy and vaccination strategies. 1590 2


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