Showing papers on "HER2/neu published in 2003"
TL;DR: There is a strong interaction, in terms of survival, between HER expression and ER expression, and the development of HER‐targeted agents, and agents targeted at the downstream signalling pathways, therefore provides new possibilities in the treatment of breast cancer.
Abstract: EGFr/HER1 and c-erbB-2/HER2 expression are associated with poor prognosis in breast cancer. The type I receptor tyrosine kinase (RTK) family to which they belong has four members (HER1–4). In this study, expression of HER1–4 and oestrogen receptor (ER) expression were determined by immunohistochemistry in 220 breast carcinomas. Elevated expression of HER1 was observed in 16.4%, HER2 in 22.8%, HER3 in 17.5%, and HER4 in 11.9% of these tumours. Patients whose tumours overexpressed HER1, 2 or 3 had reduced survival (p = <0.001), whereas those whose tumours overexpressed HER4 had increased survival (p = 0.013); 38.6% of cases overexpressed one or more of HER1, 2 or 3. HER4 was rarely overexpressed with other HERs (1.4% of cases). Cox's multiple regression analysis demonstrated that overexpression of HER1/2/3, HER4, and standard prognostic indicators independently affected survival. HER1–3 expression was related to ER negativity (p < 0.0001, χ2). Patients with ER-positive, HER1–3-positive tumours had a significantly poorer survival (p < 0.001) than those with ER-positive/HER-negative or HER4-positive tumours. Expression of HER RTKs displays complex interactions between different family members. There is a strong interaction, in terms of survival, between HER expression and ER expression. The development of HER-targeted agents (eg Herceptin, Iressa), and agents targeted at the downstream signalling pathways, therefore provides new possibilities in the treatment of breast cancer. Copyright © 2003 John Wiley & Sons, Ltd.
588 citations
TL;DR: Herceptin given as a single agent has a low activity in salivary gland tumors overexpressing Her2/neu.
213 citations
TL;DR: The determination of chromosome 17 copy number should be incorporated in assessment of Her2/neu status, as this will give an accurate measure of amplification of HER2/NEu and may also be helpful in determining suitability for breast carcinoma trials.
Abstract: Aberrations of chromosome 17 are common in breast cancer. Fluorescence in situ hybridization (FISH) enables gene or chromosome copy number to be assessed in situ in archival tissues and related to morphology and clinical outcome. In this study direct labeled DNA probes for the chromosome 17 alpha satellite and the HER2/neu gene were applied simultaneously to 5 micron sections of 214 formalin-fixed paraffin-embedded invasive primary breast carcinomas. A high proportion (54%) of invasive breast carcinomas displayed aneusomy of chromosome 17. Polysomy 17 correlated with multiple copies of HER2/neu (p = <0.001), but not with HER2/neu amplification. Eighty-six patients without HER2/neu amplification had aneusomy 17. Fifty-eight of the 86 patients that had aneusomy 17 had high HER2/neu copy number. Twelve patients with normal copy number for chromosome 17 had amplification of HER2/neu and 30 patients had amplification of HER2/neu with aneusomy 17. Aneusomy 17 was associated with grade 3 carcinoma (p = 0.008), ER negativity (p = 0.0032) and a Nottingham prognostic index of greater than 5.4 (p = 0.039) but was not associated with survival by univariate analysis. In conclusion, the determination of chromosome 17 copy number should be incorporated in assessment of HER2/neu status, as this will give an accurate measure of amplification of HER2/neu and may also be helpful in determining suitability for breast carcinoma trials.
130 citations
TL;DR: This review will focus on the signaling network mediated by HER2/neu in breast cancer and discuss the understanding of these pathways, which seem to be particularly important in mediating cell survival and growth under a wide variety of circumstances in Breast cancer.
127 citations
TL;DR: It is suggested that HSP110-ICD complex can elicit effective IFN-γ-producing T cells against spontaneous mammary tumors and that up-regulation of CD4+ CD25+ regulatory T cells may prevent complete eradication of the tumor following immunotherapy.
Abstract: Heat shock proteins (HSPs) are shown to be strong immunoadjuvants, eliciting both innate and adaptive immune responses against cancers. HSP110 is related in sequence to HSP70 and is ∼4-fold more efficient in binding to and stabilizing denatured protein substrates compared with HSP70. In the present study we evaluated the ability of a heat shock complex of HSP110 with the intracellular domain (ICD) of human HER-2/ neu to elicit effective antitumor immune responses and to inhibit spontaneous mammary tumors in FVB- neu (FVBN202) transgenic mice. The HSP110-ICD complex was capable of breaking tolerance against the rat neu protein and inhibiting spontaneous mammary tumor development. This vaccine induced ICD-specific IFN-γ and IL-4 production. Depletion studies revealed that CD8 + T cells were involved in protection against challenge with mouse mammary tumors, whereas CD4 + T cells revealed partial protection. Increased IgG2a Ab titer in the sera of tumor-free animals after vaccination and elevated CD4 + CD25 + regulatory T cells in the PBL of tumor-bearing animals suggested that IFN-γ-producing Th1 cells may be responsible for partial protection of CD4 + T cells against the mammary tumor challenge, whereas CD4 + CD25 + regulatory T cells (Th2 cells) may suppress the antitumor immune responses. Together, these results suggest that HSP110-ICD complex can elicit effective IFN-γ-producing T cells against spontaneous mammary tumors and that up-regulation of CD4 + CD25 + regulatory T cells may prevent complete eradication of the tumor following immunotherapy.
121 citations
TL;DR: Patients receiving trastuzumab were unlikely to develop new bone metastasis but were as likely as control patients to develop brain metastasis, however, patients who developed brain metastases experienced better survival compared with those patients with brain metastatic breast cancer who never received trastzumab.
105 citations
TL;DR: It is demonstrated that ER81 is acetylated by two coactivators/acetyltransferases, p300 and p300- and CBP-associated factor (P/CAF) in vitro and in vivo, indicating that both acetyltransferase and protein kinase-specific regulatory mechanisms control ER81 activity.
Abstract: The regulated expression of the ETS transcription factor ER81 is a prerequisite for normal development, and its dysregulation contributes to neoplasia. Here, we demonstrate that ER81 is acetylated by two coactivators/acetyltransferases, p300 and p300- and CBP-associated factor (P/CAF) in vitro and in vivo. Whereas p300 acetylates two lysine residues (K33 and K116) within the ER81 N-terminal transactivation domain, P/CAF targets only K116. Acetylation of ER81 not only enhances its ability to transactivate but also increases its DNA binding activity and in vivo half-life. Furthermore, oncogenic HER2/Neu, which induces phosphorylation and thereby activation of ER81, was less able to activate acetylation-deficient ER81 mutants, indicating that both acetyltransferase and protein kinase-specific regulatory mechanisms control ER81 activity. Importantly, HER2/Neu overexpression stimulates the ability of p300 to acetylate ER81, likely by inducing phosphorylation of p300 through the Ras→Raf→mitogen-activated protein kinase pathway. This represents a novel mechanism by which oncogenic HER2/Neu, Ras, or Raf may promote tumor formation by enhancing acetylation not only of ER81 but also of other downstream effector transcription factors as well as histones.
101 citations
TL;DR: The data suggest that tumorigenesis can occur in a background of defective angiogenesis but that tumors developing in such an environment may be especially sensitive to inhibitors of neu and stress-activated survival pathways.
Abstract: Id proteins bind basic helix–loop–helix transcription factors and function as dominant negative inhibitors of gene expression. Id1 and Id3 are required for the recruitment of bone marrow-derived endothelial cell precursors and tumors transplanted into Id-deficient mice demonstrate impaired angiogenesis. Mouse mammary tumor virus–neu mice were bred with Id1–/–Id3+/– mice to ascertain the role of Id1 and Id3 in mammary tumorigenesis in a more physiologically relevant model. In mammary tumors from these mice, Id1 and Id3 expression was restricted to the vascular endothelium. Id1 and Id3 deficiency did not prevent or delay tumor formation but did alter tumor phenotype. The tumors that developed in the Id-deficient mice were larger and cystic with a viable rim of tumor cells surrounding a nonviable core of cellular debris. The Hsp90 chaperone protein is required for cellular survival under condition of environmental stress and for the stability of the neu oncogene. 17-Allylamino-17-demethoxygeldanamycin, an Hsp90 inhibitor, was used to treat these mice. Whereas 17-allylamino-17-demethoxygeldanamycin only modestly delayed the growth of established mammary tumors in WT mice for Id, tumor suppression was dramatically more effective in an Id1- or Id3-deficient background. These data suggest that tumorigenesis can occur in a background of defective angiogenesis but that tumors developing in such an environment may be especially sensitive to inhibitors of neu and stress-activated survival pathways. Thus angiogenesis inhibitors in combination with inhibitors of Hsp90 function should be evaluated for the treatment of advanced breast cancer.
94 citations
TL;DR: The results show that the presence of increased levels of HER2/neu in SSs is associated with a more favorable clinical course and the role of this oncogene in soft tissue tumors remains poorly understood.
93 citations
TL;DR: A novel mechanism by which oncogenic HER2/Neu, in collaboration with ER81, can induce carcinogenesis through Smad7 up-regulation is uncovered.
90 citations
TL;DR: Although the optimal treatment for HER2/neu-overexpressing cancer patients remains elusive, the initial success of trastuzumab indicates that HER2 /neu is a good target for cancer therapy.
TL;DR: It is suggested that HER2/neu abnormalities occur prior to and persist with the onset of muscle-invasive disease, and anti-HER2/NEu therapy might be of use in the treatment of TCC.
Abstract: The mortality from transitional cell carcinoma (TCC) of the urinary bladder increases significantly with the progression of superficial or locally invasive disease (pTa/pT1) to detrusor muscle-invasive disease (pT2+). The most common prognostic markers in clinical use are tumour stage and grade, which are subject to considerable intra- and interobserver variation. Polysomy 17 and HER2/neu gene amplification and protein overexpression have been associated with more advanced disease. Standardised techniques of fluorescence in situ hybridisation and immunohistochemistry, which are currently applied to other cancers with a view to offering anti-HER2/neu therapies, were applied to tumour pairs comprising pre- and postinvasive disease from 25 patients undergoing treatment for bladder cancer. In the preinvasive tumours, increased HER2/neu copy number was observed in 76% of cases and increased chromosome 17 copy number in 88% of cases, and in the postinvasive group these values were 92 and 96%, respectively (not significantly different P=0.09 and 0.07, respectively). HER2 gene amplification rates were 8% in both groups. Protein overexpression rates were 76 and 52%, respectively, in the pre- and postinvasive groups (P=0.06). These results suggest that HER2/neu abnormalities occur prior to and persist with the onset of muscle-invasive disease. Gene amplification is uncommon and other molecular mechanisms must account for the high rates of protein overexpression. Anti-HER2/neu therapy might be of use in the treatment of TCC.
TL;DR: Results suggest that vaccines including ECD(HER2) and Ab-cytokine fusion proteins may be used to elicit both humoral and cell-mediated responses against HER2/neu.
TL;DR: The data suggest that Herceptin is an effective first-line single-agent therapy for a predictable cohort of metastatic breast cancers and can therefore be used as a platform for therapeutic discovery against tumors that overexpress HER2.
Abstract: Overexpression of the HER2/Neu (ErbB2) proto-oncogene is associated with breast cancer progression and poor patient prognosis. Herceptin (trastuzumab) is a humanized IgG1 against the ectodomain of the HER2 receptor. In combination with chemotherapy, it induces regression of HER2-overexpressing metastatic breast tumors and prolongs patient survival. Single-agent Herceptin in patients with HER2-amplified breast tumors also induces a definite objective response and clinical benefit rates, and is well tolerated. These data suggest that Herceptin is an effective first-line single-agent therapy for a predictable cohort of metastatic breast cancers and can therefore be used as a platform for therapeutic discovery against tumors that overexpress HER2.
TL;DR: The administration of epirubicin and docetaxel in the neoadjuvant setting is not associated with significant changes of HER2/neu status in primary breast cancer, and drug resistance or sensitivity is not induced by modulation of Her2/NEu expression.
Abstract: Background. In primary breast cancer, the expression levels of biological markers relevant to the progression of the disease may be altered by administration of anticancer drugs. Since neoadjuvant chemotherapy with epirubicin and docetaxel is increasingly used in advanced breast cancer, our purpose was to assess the influence of this neoadjuvant chemotherapy on the expression of the growth factor receptor HER2/neu.
Patients and methods. We investigated changes of HER2/neu status by immunohistochemistry (IHC) and applied additional fluorescence in situ hybridization (FISH) in patients with potential modulation of HER2/neu status after administration of neoadjuvant chemotherapy with docetaxel and epirubicin in 97 breast cancer patients. The influence of neoadjuvant chemotherapy on HER2/neu expression was calculated by correlation of HER2/neu status before and after chemotherapy.
Results. The accuracy of HER2/neu assessment before and after neoadjuvant chemotherapy by IHC combined with FISH analysis in selected cases was 100%. The evaluation of HER2/neu status in these patients by IHC alone yielded accuracy of 93%. Neoadjuvant chemotherapy with epirubicin and docetaxel caused no significant modulation of HER2/neu status (p = 0.66).
Discussion. The administration of epirubicin and docetaxel in the neoadjuvant setting is not associated with significant changes of HER2/neu status in primary breast cancer. As a consequence, drug resistance or sensitivity is not induced by modulation of HER2/neu expression. Moreover, the time of assessment of the HER2/neu status is not a critical factor under neoadjuvant therapy with epirubicin and docetaxel.
TL;DR: Translational experiments using rodent breast cancer models suggest COX-2 inhibition to be an effective strategy for both prevention and treatment of experimental breast cancers, and Manipulation of Cox-2 gene dosage by using transgenic overexpression and knockout approaches has revealed an important role for Cox- 2 in tumorigenesis.
Abstract: The inducible prostaglandin synthase cyclooxygenase-2 (COX-2) is normally expressed predominantly in kidney and brain, and also has important roles in reproduction and inflammation. COX-2 misexpression has been observed in numerous human cancers, including the majority of colorectal cancers. Recently, COX-2 overexpression has been described in human breast cancer. COX-2 is present in about 40% of invasive breast carcinomas, particularly those that overexpress HER2/neu, and COX-2 expression correlates with poor patient prognosis. Manipulation of Cox-2 gene dosage by using transgenic overexpression and knockout approaches has revealed an important role for Cox-2 in tumorigenesis. Furthermore, translational experiments using rodent breast cancer models suggest COX-2 inhibition to be an effective strategy for both prevention and treatment of experimental breast cancers. Since COX-2 can contribute to multiple facets of tumorigenesis, including angiogenesis, several mechanisms are likely to underlie the anticancer action of COX inhibitors. Thus, selective COX-2 inhibitors offer considerable promise for the prevention and treatment of human breast cancer.
TL;DR: The ability to easily create, directly from plasmid components, an oncolytic replicating VSV with a restricted host cell range is demonstrated.
TL;DR: The role of new biomarkers, such as p53, HER2/neu, angiogenesis, and the proliferation index value, is promising; however, the clinical value of their determination must be provided by prospective clinical studies.
TL;DR: Concerning the clinical outcome, Her2/neu overexpression may be regarded as a prognostic factor in differentiated thyroid carcinomas and application of Herceptin could lead to new successful therapeutic concepts for a number of patients with progressive thyroid cancer.
Abstract: To investigate the prognostic value of Her2/neu expression in differentiated thyroid carcinomas 103 patients were retrospectively investigated. All of them received surgical and an identical follow-up treatment. The patients with papillary and follicular thyroid cancer were further separated into two groups concerning their clinical development, including one group without distant metastasis (follow-up of minimum 8 years). The second group presented with distant metastases as a sign of an aggressive behaviour. Her2/neu was immunohistochemically detected on sections from formalin-fixed, paraffin-embedded tissues using c-erbB-2/Her-2/neu oncoprotein Ab-17 monoclonal antibody (mAb). In statistical analysis using the Mann-Whitney U-test and chi(2) test, Her2/neu protein overexpression was significantly correlated with prognosis. Both tumour entities without distant metastases showed significantly less cytoplasmic immunostaining than patients with development of metastases. Concerning the clinical outcome, Her2/neu overexpression may be regarded as a prognostic factor in differentiated thyroid carcinomas. Moreover, in addition to standard radio-iodine elimination therapy, application of Herceptin could lead to new successful therapeutic concepts for a number of patients with progressive thyroid cancer.
TL;DR: It is reported that HER2/neu reduces the ability of 4-HPR to induce apoptosis in breast cancer cells, and that one mechanism by which HER2-neu increases the resistance of Breast cancer cells to 4- HPR is by decreasing NOSII-mediated NO production.
Abstract: The retinoid N-(4-hydroxyphenyl)retinamide (4-HPR also known as fenretinide) is a potent inducer of apoptosis in breast cancer cells. We observed a 4.5-fold reduction in 4-HPR-mediated apoptosis in MCF-7 breast cancer cells transfected with HER2/neu (MCF-7/HER2) as compared with the parental MCF-7 (MCF-7/WT) cells. Blocking HER2/neu with trastuzumab (Herceptin) led to a six-fold increase in 4-HPR-induced apoptosis in HER2/neu-overexpressing cells. These data indicate that HER2/neu reduces the sensitivity of breast cancer cells to 4-HPR. We showed previously that nitric oxide (NO) is essential for 4-HPR to induce apoptosis in breast cancer cells. The inhibitory effects of the 4-HPR and trastuzumab combination correlated with the amount of NO produced in HER2/neu-overexpressing cells. When a NO synthase (NOS) inhibitor was used to block NO production, decreased apoptosis by the 4-HPR and trastuzumab combination was observed. Furthermore, 4-HPR-mediated NOSII expression was lower in MCF-7/HER2 than MCF-7/WT cells, but was increased by trastuzumab in HER2/neu-overexpressing cells. Here we report the novel findings that HER2/neu reduces the ability of 4-HPR to induce apoptosis in breast cancer cells, and that one mechanism by which HER2/neu increases the resistance of breast cancer cells to 4-HPR is by decreasing NOSII-mediated NO production.
TL;DR: It is feasible and safe to generate and administer HER2-loaded DCs to patients with advanced HER2/neu-expressing malignancies and high-risk breast cancer, and more potent DC loading and maturation strategies will be necessary to optimize these vaccines.
TL;DR: Although the optimal treatment for HER2/neu-overexpressing cancer patients remains elusive, the initial success of trastuzumab indicates that HER2 /neu is a good target for cancer therapy.
TL;DR: Details of this novel biologic agent are reviewed, in conjunction with an overview of clinical studies performed in Japan, to show that trastuzumab plus chemotherapy as a first-line treatment for metastatic breast cancer significantly improved response rate, time to disease progression, and overall survival compared with chemotherapy alone.
Abstract: The HER2 gene is overexpressed or amplified in approximately 30% of breast cancers. Breast cancer patients with HER2 overexpression or amplification have shortened disease-free and overall survivals. The HER2 protein is thought to be a unique and useful target for antibody therapy of cancers overexpressing the HER2 gene. The recombinant humanized anti-HER2 monoclonal antibody, trastuzumab (Herceptin) is now available for clinical use. In a large phase II trial, trastuzumab produced a favorable response rate as a single agent in patients with metastatic breast cancer who had received one or two prior chemotherapies. Furthermore, a large phase III trial showed that trastuzumab plus chemotherapy as a first-line treatment for metastatic breast cancer significantly improved response rate, time to disease progression, and overall survival compared with chemotherapy alone. As a single agent and in combination with chemotherapy, trastuzumab was generally well tolerated. Thus, trastuzumab plays an important role in the treatment strategy of metastatic breast cancer overexpressing HER2 protein. In this article, details of this novel biologic agent are reviewed, in conjunction with an overview of clinical studies performed in Japan.
Journal Article•
TL;DR: Findings suggest a decreasing impact of Her2/neu oncoproteins correlating to dedifferentiation, reflecting the aggressive biological behaviour of these tumors.
Abstract: The Her2/neu expression in poorly-differentiated thyroid carcinomas (PDTC) and in anaplastic thyroid cancer (ATC) was investigated retrospectively. Tumors of 25 patients suffering from PDTC and 25 from ATC were evaluated, including 15 cases of PDTC with highly-differentiated tumor parts. Her2/neu levels were immunohistochemically detected on formalin-fixed, paraffin-embedded tissues using c-erbB-2 / Her-2/neu Oncoprotein Ab-17 monoclonal antibody(mAb). In statistical analysis using 1-way ANOVA, Her2/neu protein overexpression was highly significantly correlated with the differentiation status of the investigated tumor parts. Whereas ATCs showed only few positive tumor cells, PDTCs presented with large reacting tumor areas and highly-differentiated parts of PDTCs revealed the highest staining intensity. These findings suggest a decreasing impact of Her2/neu oncoproteins correlating to dedifferentiation, reflecting the aggressive biological behaviour of these tumors.
TL;DR: Her2/neu contributes to the growth of some Wilms' tumors, and an important mechanism of its action is promotion of angiogenesis.
TL;DR: Analysis of the expression of matrix metalloproteinase-2, −9 and TIMP-1 in 154 patients with head and neck squamous cell carcinoma suggested that MMP-2 had a more important function than M MP-9 in tumor invasion and metastasis; that HER2/neu might serve as a biomarker for poor prognosis in HNSCC.
Abstract: This study aimed to explore the molecular mechanism in tumor invasion and metastasis. The expression of matrix metalloproteinase-2, -9 (MMP-2, MMP-9), tissue inhibitor-1 of matrix metalloproteinase (TIMP-1), cell adhesion molecule 44 variant 6 (CD44v6), HER2/neu and p53 was investigated in 154 patients with head and neck squamous cell carcinoma (SCC) by ABC and ImmunoMax immunohistochemical method. Their clinical relevance and correlation were analysed. The expression of MMP-2, MMP-9, TIMP-1, CD44v6, HER2/neu and p53 was found in cancer cells in 87.01%, 85.71%, 68.18%, 98.05%, 55.19% and 50.65% cases respectively. Linear regression and correlation analysis revealed that there was close positive relationship (P<0.05) between the expression of MMP-2 and MMP-9, TIMP-1 and CD44v6, HER2/neu and MMP-9, MMP-2 and p53. Up-regulation of MMP-2 was accompanied by advanced T stage (P<0.01). There was also a trend of MMP-2 expression being related with tumor metastasis. Increased expression of HER2/neu was found in patients with tumor recurrence(P<0.05). The expression of TIMP-1 was higher in laryngeal cancer than that in pharyngeal cancer, and higher in keratinizing and non-keratinizing SCC than that in basaloid SCC(P<0.05). These findings suggested that MMP-2 and MMP-9, HER2/neu and MMP-9, MMP-2 and p53 had a coordinate function in aggression of tumor; that MMP-2 had a more important function than MMP-9 in tumor invasion and metastasis; and that HER2/neu might serve as a biomarker for poor prognosis in HNSCC.
TL;DR: Her2/neu expression does not correlate with prognosis of soft tissue sarcomas and its evaluation for tumor prognosis as well as for the identification for adjuvant therapeutic strategies does not appear warranted at this point.
Abstract: Background: The expression of HER2/neu has been identified as a prognostic factor in several malignant diseases. However, only sparse data exist correlating HER2/neu expression in s