Neu Oncoprotein Research Articles

Lack of HER-2/neu expression in Hodgkin and non-Hodgkin lymphoma.

Overexpression of HER-2/neu oncoprotein, a tyrosine kinase receptor, occurs in a variety of human cancers and has been shown to play a critical role in their development. This overexpression is usually associated with poor clinical outcome. The significance of HER-2/neu in lymphomas is unknown. The aim of this study was to evaluate the expression of HER-2/neu in the malignant lymphomas: non-Hodgkin and Hodgkin lymphomas. We studied formalin-fixed, paraffin-embedded tissue from 50 patients with lymphoma. Forty-two specimens were from patients with various types of non-Hodgkin lymphoma, and 8 were from patients with Hodgkin lymphoma. HER-2/neu expression was examined by an immunohistochemical technique using the HercepTest. None of the specimens demonstrated overexpression or even any expression of HER-2/neu. Reactive plasma cells showed cytoplasmic staining, which was not found in malignant plasma cells from patients with multiple myeloma. Non-Hodgkin and Hodgkin lymphomas do not express the HER-2/neu oncoprotein. This finding suggests that HER-2/neu does not play a role in these diseases.

Elevated Serum HER-2/neu Level Predicts Decreased Response to Hormone Therapy in Metastatic Breast Cancer

PURPOSE: To determine the effect of elevation of serum HER-2/neu on response to hormone therapy. PATIENTS AND METHODS: Seven hundred nineteen metastatic patients with estrogen receptor–positive (ER+), progesterone receptor–positive, or both or ER status unknown breast cancer were randomized in three independent clinical trials to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An automated enzyme-linked immunosorbent assay specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum levels. RESULTS: Two hundred nineteen patients (30%) had elevated serum HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of healthy women as an upper limit. Response to treatment was available for 711 patients. The response rate (complete responses plus partial responses plus stable disease) to endocrine therapy was 45% in 494 patients with nonelevated and 23% in 217 patients with ele...

Efficacy of vaccination with plasmid DNA encoding for HER2/ neu or HER2/ neu-EGFP fusion protein against prostate cancer in rats

Despite early diagnosis and improved therapy, 31,500 men will die from prostate cancer (PC) this year. The HER2/ neu oncoprotein is an important effector of cell growth found in the majority of high-grade prostatic tumors and is capable of rendering immunogenicity. The antigenicity of this oncoprotein might prove useful in the development of PC vaccines. Our goal is to prove the principle that a single DNA vaccine can provide reliable immunity against PC in the MatLyLu (MLL) translational tumor model. The parental rat MatLyLu PC cell line expresses low to moderate levels of the rat neu protein. To simulate in vivo human PC, MatLyLu cells were transfected with a truncated sequence of human HER2/ neu cDNA cloned into the pCI-neo vector. This HER2/ neu cDNA sequence encodes the first 433 amino acids of the extracellular domain (ECD). MatLyLu cells were also transfected with the same HER2/ neu cDNA sequence cloned into the N1-terminal sequence of EGFP reporter gene to produce a fusion protein. The partial ECD sequence of HER2/ neu includes five rat major histocompatibility (MHC)-II-restricted peptides with complete human-to-rat cross-species homology. The HER2/ neu protein overexpression was documented by Western Blot analysis, and the expression of fusion protein was monitored by confocal microscopy and fluorimetry. Vaccination with a single injection of HER2/ neu cDNA protected 50% of animals against HER2/ neu-MatLyLu tumors ( P<0.01). When the tumor cells were engineered to express HER2/ neu-EGFP fusion protein, the antitumor immunity was enhanced, as following vaccination with HER2/ neu-EGFP cDNA, 80% of these rats rejected HER2/ neu-EGFP-MatLyLu ( P<0.001). Both vaccines induced HER2/ neu-specific antibody titers. Rats vaccinated with EGFP-cDNA rejected 80% of EGFP-MatLyLu tumors and, interestingly, 40% of HER2/ neu-MatLyLu tumors. None of the cDNA vaccines induced immunity against parental MatLyLu cells. Our data clearly demonstrate that a single injection of HER2/ neu-EGFP cDNA is a very effective vaccine against PC tumors expressing the cognate tumor-associated antigen (TA). The antitumor immunity is significantly more pronounced if the tumors express xenogeneic HER2/ neu-EGFP fusion protein as opposed to only the syngeneic HER2/ neu oncoprotein. Our data suggests that the HER2/ neu-EGFP-MatLyLu tumor is a potential animal tumor model for investigating therapeutic vaccine strategies against PC in vivo and demonstrates the limitations of a cDNA vaccine only encoding for MHC-II-restricted HER2/ neu-ECD sequence peptides.

Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer

HER2/ neu amplification/overexpression confers more aggressive and malignant characteristics on breast cancer cells. Patients with HER2/ neu-amplified breast cancer have a worse prognosis than those with normal HER2/ neu expression. Over the past decade, the intracellular signaling pathways associated with this growth factor receptor have been elucidated. Multiple therapeutic strategies that target the HER2/ neu oncoprotein are under development. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), a humanized monoclonal antibody that binds to the extracellular domain of the HER2/ neu receptor, has undergone phase I, II, and III clinical trials. These studies have shown that, as a single agent, trastuzumab has substantial and reproducible antitumor activity in HER2/ neu-amplified metastatic breast cancer. In addition, when added to chemotherapy, trastuzumab improves antitumor efficacy as measured by time to progression, response rate, and survival. Additional chemotherapy/ trastuzumab combinations are under active evaluation, and new schedules of administration are being tested. Thus, trastuzumab is the first successful example of molecularly targeted therapy in the management of metastatic breast cancer.

Study of pretreatment serum levels of HER‐2/neu oncoprotein as a prognostic and predictive factor in patients with advanced nonsmall cell lung carcinoma

BACKGROUND HER-2/neu tissue overexpression is found in nearly 15% of patients with nonsmall cell lung carcinoma and is reported to affect prognosis adversely in surgical series. However, the prognostic role of serum HER-2/neu oncoprotein, particularly in patients with advanced lung carcinoma, remains unknown. This study was designed to assess the potential value of measuring serum levels of HER-2/neu oncoprotein in predicting response to treatment and survival in patients with locally advanced and metastatic nonsmall cell lung carcinoma. METHODS Baseline serum HER-2/neu levels (fm/mL) were studied using an enzyme-linked immunosorbent assay method in 84 patients with newly diagnosed, advanced nonsmall cell lung carcinoma who underwent chemotherapy. RESULTS The patients enrolled in the study included 76 males and 8 females, with a median age of 62 years (range, 36–73 years) and a median performance status of 1. Fifty patients (59.5%) had nonsquamous histology, and 34 patients (40.5%) had squamous cell carcinoma. Thirty-four patients (40.5%) had Stage III disease, and 50 patients (59.5%) had Stage IV disease. The mean baseline value of HER-2/neu in the whole series was 56.1 fm/mL (range, 13.0–103.8 fm/mL). HER2 immunohistochemistry on paraffin embedded tissue was performed in 18 patients. HER-2/neu tissue overexpression was found in only one patient, who also showed high serum levels (102 fm/mL). No correlation was observed between protein serum quantitation and gender, age, histology, stage, performance status, leukocyte count, or smoking. Nonresponding and responding patients exhibited similar oncoprotein levels (median, 57.6 fm/mL vs. 51.9 fm/mL, respectively). The overall survival rate was 42.5% at 1 year and 12% at 2 years, with a median survival duration of 10 months. At univariate analysis, high HER-2/neu serum levels were associated with an unfavorable survival outcome. Using a cut-off point for HER-2/neu of 73.0 fm/mL (corresponding to the 80th percentile of protein concentration), the survival of patients who had higher serum levels of HER-2/neu was significantly worse compared with patients who had lower serum levels (median, 7.1 months vs. 10.9 months; P = 0.004). Multivariate analysis confirmed the independent predictive value of serum HER-2/neu concentration as a negative prognostic factor (P = 0.02). CONCLUSIONS High pretreatment levels of HER-2/neu oncoprotein are associated with an adverse prognostic impact on survival in patients with locally advanced or metastatic nonsmall cell lung carcinoma. Cancer 2001;92:1896–904. © 2001 American Cancer Society.

Expression of HER-2/NEU oncoprotein in familial and non-familial breast cancer.

The HER-2/neu proto-oncogene amplification or oncoprotein overexpression is an important prognostic factor and a predictive factor for resistance to endocrine therapy and adjuvant chemotherapy in breast cancers. Moreover, it is an entry criterion in the assessment of patients for whom Herceptin (Trastuzumab) treatment is considered. The overexpression rate of HER-2/neu oncoprotein has been identified in 10% to 40% of human breast cancers. In Taiwan, a higher grade of pathobiologic characteristics of familial breast cancer was also noted than that found in the non-familial group. It is worthwhile to evaluate whether the overexpression is more frequent in familial breast cancers. Fifty-six familial and 111 non-familial breast cancers were studied between 1990 and 1999 to assess both the overexpression of HER-2/neu oncoprotein immunohistochemically and the correlation with the histological type, grade and stage of breast carcinoma. The overexpression rate is higher in the familial breast cancer group (50.0%) when compared with non-familial breast cancer group (36.9%), which did not prove to be statistically significant (P = 0.1068). However, when the infiltrating ductal carcinomas of both groups are compared, it is statistically significant (52.3% vs. 33.7%, P = 0.0429). Overexpression correlated with node status and histological grade of infiltrating ductal carcinomas in non-familial and overall breast cancers. It also correlated with nuclear pleomorphism and mitotic counts, but not tubule formation or tumor size. All 3 cases of Paget's disease revealed overexpression, whereas all 12 cases of mucinous and one case of metaplastic carcinoma and one case of medullary carcinoma were negative. The overexpression rate was higher both in familial and non-familial intraductal carcinomas (57.1% vs. 73.3%, P = 0.4716). No statistical difference was identified between the 2 subsets. A case of infiltrating ductal carcinoma combined with intraductal carcinoma revealed heterogeneous staining in the component of ductal carcinoma in situ, while the invasive component did not. This suggests that overexpression decreases within individual tumors as they evolve from in situ to invasive lesioins. The HER-2/neu may imply a different role in intraductal carcinoma, Paget's disease and invasive duct carcinoma. Although the overexpression rate of HER-2/neu oncoprotein of familial breast cancer was not significantly higher than that of the non-familial group, it is appropriate to evaluate the rate of HER-2/neu overexpression according to the histological type of breast cancers from familial breast cancer and non-familial breast cancer. The prognoses will be needed for future evaluation.

Study of pretreatment serum levels of HER-2/neu oncoprotein as a prognostic and predictive factor in patients with advanced nonsmall cell lung carcinoma

HER-2/neu tissue overexpression is found in nearly 15% of patients with nonsmall cell lung carcinoma and is reported to affect prognosis adversely in surgical series. However, the prognostic role of serum HER-2/neu oncoprotein, particularly in patients with advanced lung carcinoma, remains unknown. This study was designed to assess the potential value of measuring serum levels of HER-2/neu oncoprotein in predicting response to treatment and survival in patients with locally advanced and metastatic nonsmall cell lung carcinoma. Baseline serum HER-2/neu levels (fm/mL) were studied using an enzyme-linked immunosorbent assay method in 84 patients with newly diagnosed, advanced nonsmall cell lung carcinoma who underwent chemotherapy. The patients enrolled in the study included 76 males and 8 females, with a median age of 62 years (range, 36-73 years) and a median performance status of 1. Fifty patients (59.5%) had nonsquamous histology, and 34 patients (40.5%) had squamous cell carcinoma. Thirty-four patients (40.5%) had Stage III disease, and 50 patients (59.5%) had Stage IV disease. The mean baseline value of HER-2/neu in the whole series was 56.1 fm/mL (range, 13.0-103.8 fm/mL). HER2 immunohistochemistry on paraffin embedded tissue was performed in 18 patients. HER-2/neu tissue overexpression was found in only one patient, who also showed high serum levels (102 fm/mL). No correlation was observed between protein serum quantitation and gender, age, histology, stage, performance status, leukocyte count, or smoking. Nonresponding and responding patients exhibited similar oncoprotein levels (median, 57.6 fm/mL vs. 51.9 fm/mL, respectively). The overall survival rate was 42.5% at 1 year and 12% at 2 years, with a median survival duration of 10 months. At univariate analysis, high HER-2/neu serum levels were associated with an unfavorable survival outcome. Using a cut-off point for HER-2/neu of 73.0 fm/mL (corresponding to the 80th percentile of protein concentration), the survival of patients who had higher serum levels of HER-2/neu was significantly worse compared with patients who had lower serum levels (median, 7.1 months vs. 10.9 months; P = 0.004). Multivariate analysis confirmed the independent predictive value of serum HER-2/neu concentration as a negative prognostic factor (P = 0.02). High pretreatment levels of HER-2/neu oncoprotein are associated with an adverse prognostic impact on survival in patients with locally advanced or metastatic nonsmall cell lung carcinoma.

Salivary duct carcinoma--a highly aggressive salivary gland tumor with HER-2/neu oncoprotein overexpression.

Salivary duct carcinoma (SDC) is a highly malignant salivary gland tumor with aggressive clinical behavior, and is characterized by its histological resemblance to invasive ductal carcinoma of the breast. Overexpression and/or amplification of proto-oncogene Her2/neu has been shown to influence both prognosis and treatment of breast cancer. Since salivary duct carcinoma and ductal breast carcinoma share many common characteristics, HER2/neu overexpression might also be important in SDC. However, data on the expression of c-erbB2/HER2/neu in salivary gland tumors are still scarce. Therefore, we have evaluated 15 cases of salivary duct carcinomas (SDC) for HER2/neu overexpression using immunohistochemistry with the HercepTest. Overexpression, identified as strong or moderate membrane immunostaining, was observed in all but one case of SDC in most neoplastic cells. Thus, our study suggests that anti-HER2/neu therapy with Herceptin is beneficial for patients with aggressive salivary duct carcinoma.

Relevance of p185 HER-2/neu oncoprotein quantification in human primary breast carcinoma.

The c-erbB-2 proto-oncogene encodes a transmembrane protein tyrosine kinase receptor of 185 kDa (p185) and has been associated with several types of human cancers. In human breast cancer, overexpression of p185 occurs in 15-30% of cases, correlates with poor prognostic factors and characterizes breast cancers with a more aggressive behavior. Overexpression of p185 is usually associated with c-erbB-2 amplification, though it may occur independently and thus define subpopulations of breast cancers which might be of clinical interest. p185 expression is usually detected by immunohistochemistry (IHC) and few studies have been carried out to evaluate the p185 content of breast cancers with an ELISA technique. In this context, we showed, in 106 breast cancer samples, that p185 was expressed at high levels in 13.2%, intermediate levels in 55.7% and negative ones in 31.1% of cases. All p185 positive samples showed a c-erbB-2 oncogene amplification while none of the p185 negative samples and only 4% of p185 imtermediate samples had an amplification of c-erbB-2. p185 expression is significantly correlated with the negativity of estrogen and progestrone receptors, with high levels of cathepsin D and in some conditions with axillary nodal involvement. Thus, using the p185 ELISA assay, the c-erbB-2 status of breast cancers can be defined and moreover a subset can be discriminated which is characterized by intermediate levels of p185 and absence of c-erbB-2 amplification. The quantitative approach towards p185 in breast cancers affords the possibility of identifying more appropriately patients with high or low risk and thus permits adaptation of therapeutic regimens.

Developments in chemotherapy of breast cancer.

Breast carcinoma is moderately sensitive to multiple antitumor agents. Cytotoxic combination regimens developed in the 1970s were shown to produce higher response rates and longer durations of response and survival than single-agent therapy. These regimens became the standard of care for the management of metastatic, hormone-refractory breast carcinoma, and more recently, for primary breast carcinoma. Randomized trials also have demonstrated that anthracycline-containing combinations were more effective than combinations without anthracyclines. The development of several new cytotoxic agents and novel antitumor strategies prompted this review. The author conducted a computerized literature search of MEDLINE and CANCERLIT and also reviewed the abstracts of major oncology meetings (ASCO, American Association for Cancer Research, ESMO, and San Antonio Breast Cancer Symposium) over the past 10 years. Effective new cytotoxic drugs include the taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and capecitabine. The identification of specific molecular abnormalities (HER-2/neu or epidermal growth factor receptor [EGFR] overexpression) led to the development of targeted therapeutic intervention (monoclonal antibodies and tyrosine kinase inhibitors). Trastuzumab, a monoclonal antibody against the HER-2/neu oncoprotein, produced objective regression in 15-20% of patients with HER-2/neu-overexpressing breast carcinoma and improved the efficacy of paclitaxel. Other productive directions of therapeutic research include inhibition of intracellular signaling, interference with tumor angiogenesis, cell cycle regulation, and the development of vaccines. Expanded understanding of the biology of breast carcinoma led to the development of rational therapeutic interventions, many of which are currently under active clinical development.

Developments in chemotherapy of breast cancer

BACKGROUND Breast carcinoma is moderately sensitive to multiple antitumor agents. Cytotoxic combination regimens developed in the 1970s were shown to produce higher response rates and longer durations of response and survival than single-agent therapy. These regimens became the standard of care for the management of metastatic, hormone-refractory breast carcinoma, and more recently, for primary breast carcinoma. Randomized trials also have demonstrated that amthracycline-containing combinations were more effective than combinations without anthracyclines. The development of several new cytotoxic agents and novel antitumor strategies prompted this review. METHODS The author conducted a computerized literature search of MEDLINE and CANCERLIT and also reviewed the abstracts of major oncology meetings (ASCO, American Association for Cancer Research, ESMO, and San Antonio Breast Cancer Symposium) over the past 10 years. RESULTS Effective new cytotoxic drugs include the taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and capecitabine. The identification of specific molecular abnormalities (HER-2/neu or epidermal growth factor receptor [EGFR] overexpression) led to the development of targeted therapeutic intervention (monoclonal antibodies and tyrosine kinase inhibitors). Trastuzumab, a monoclonal antibody against the HER-2/neu oncoprotein, produced objective regression in 15–20% of patients with HER-2/neu–overexpressing breast carcinoma and improved the efficacy of paclitaxel. Other productive directions of therapeutic research include inhibition of intracellular signaling, interference with tumor angiogenesis, cell cycle regulation, and the development of vaccines. CONCLUSIONS Expanded understanding of the biology of breast carcinoma led to the development of rational therapeutic interventions, many of which are currently under active clinical development. Cancer 2000;88:3073–9. © 2000 American Cancer Society.

HER-2/neu is expressed in human renal cell carcinoma at heterogeneous levels independently of tumor grading and staging and can be recognized by HLA-A2.1-restricted cytotoxic T lymphocytes

The HER-2/neu oncoprotein, a 185 kDa membrane-associated tyrosine kinase with extensive homology to the epidermal growth factor receptor (EGF-R), is overexpressed in breast and ovarian carcinomas. Its overexpression is closely associated with poor prognosis in the course of disease. Here we demonstrate HER-2/neu overexpression in both established cell lines and biopsy material obtained from renal epithelial tumors. Immunohistochemical analysis of human kidney tumor lesions using 2 HER-2/neu-specific antibodies revealed HER-2/neu expression in more than 40% of primary epithelial renal tumors and more than 30% of primary renal cell carcinoma (RCC) specimens. A distinctive HER-2/neu expression pattern was found in different subtypes of kidney tumors with the highest frequency in chromophilic and chromophobic RCC, but neither associated with disease stage nor tumor grade. Eight of 10 RCC cell lines expressed significant levels of HER-2/neu mRNA and protein, but at a lower level compared with HER-2/neu overexpressing ovarian carcinoma cells. To evaluate the immune response against HER-2/neu expressing HLA-A2-positive (HLA-A2(+)) RCC cells, allogeneic HLA-A2-restricted cytotoxic T-lymphocyte (CTL) lines generated by pulsing dendritic cells with 3 different HER-2/neu-derived peptides, (HER-2(9.369), HER-2(9.435) and HER-2(9.689), were utilized in chromium-release assays. Specific lysis of HER-2/neu expressing HLA-A2(+) RCC cell lines was mediated by CTL lines specific for each of these 3 HER-2/neu-derived epitopes. The fine specificity of 2 CTL clones was defined to the epitopes HER-2(9.435) and HER-2(9.689). Their specificity was then confirmed by cold target inhibition assays. In addition, CTL-mediated lysis was enhanced by pulsing tumor cells with exogenous HER-2/neu-specific peptides. Our data suggest that (i) HER-2/neu is heterogeneously expressed in different subtypes of RCC, (ii) HER-2/neu is naturally processed by RCC and (iii) HER-2/neu epitopes presented by RCC can be recognized by HLA-A2-restricted, HER-2/neu-specific CTL.

La expresión de la molécula de adhesión CD44v6 en carcinomas ductales infiltrantes de mama se asocia con la hormonodependencia. Nuestra experiencia con 168 casos

In order to investigate the possible hormone-dependence of CD44v6 in human breast cancer, we assayed the concentrations of this isoform in the membrane fraction of 168 invasive ductal carcinomas (IDC) and in 26 normal breast tissue samples, 18 fibradenomas (FAD), 3 fibrocystic disease specimens (FD), 7 mucinous carcinomas and 4 medullary carcinomas using the ELISA method. The results were compared with those of the estrogen (ER) and progesterone (PR) receptors, pS2, tissue type plasminogen activator (t-PA), cathepsin D, epidermal growth factor receptor (EGFR) and c-erbB2/neu oncoprotein concentrations. Menopausal status, size of the tumor in the cases of cancers, axillary lymph node involvement, histologic grade, ploidy, cellular synthesis phase, multifocality and multicentricity were also considered as variables. The cut-off value for CD44v6-positivity was set at 5 ng/mg prt. membrane protein content. 64/138 (38.1%) infiltrating ductal carcinomas scored positive. This was significantly higher than for the normal breast tissue (0/26; p: 0.0001), similar to that seen in the FAD (3/18), fibrocystic disease (0/3), infiltrating mucinous carcinomas (4/7) and lobular (3/15) and significantly lower than for the infiltrating medullary carcinomas (4/4; p: 0.027). There were no significant differences with the other groups of tissues studied. Furthermore, CD44v6-positive IDC showed significantly higher concentrations of ER, PR and cathepsin D and lower (p: 0.051) concentrations of EGFR when compared to their CD44v6-negative counterparts. The significant coexpression of ER, PR and cathepsin D seems to indicate a possible role for hormonal regulation of CD44v6 expression while the role of pS2 and t-PA, estrogen related proteins, was very reduced.

Radioiodinated antibody targeting of the HER-2/ neu oncoprotein: effects of labeling method on cellular processing and tissue distribution

Monoclonal antibody (MAb) internalization can have a major effect on tumor retention of radiolabel. Two anti-HER-2/ neu MAbs (TA1 and 520C9) were radioiodinated using the iodogen, N-succinimidyl 5-iodo-3-pyridinecarboxylate (SIPC), and tyramine-cellobiose (TCB) methods. Paired-label studies compared internalization and cellular processing of the labeled MAbs by SKOv3 9002-18 ovarian cancer cells in vitro. Intracellular radioiodine activity for 520C9 was up to 2.6 and 3.0 times higher for SIPC and TCB labeling, respectively, compared with iodogen. Likewise, intracellular activity for TA1 was up to 2.3 and 2.9 times higher with the SIPC and TCB methods compared with iodogen labeling. Unfortunately, similar advantages in tumor accumulation were not achieved in athymic mice bearing SKOv3 9008-18 ovarian cancer xenografts.

Antigen-specific recall urticaria to a peptide-based vaccine

Recall urticaria (RU) is a localized urticarial response that occurs at a site of previous antigen injection on reexposure to that antigen at a remote site.1 The response is rare and typically associated with allergy immune therapies. The mechanism for RU is poorly understood, but possibilities include increased accumulation and degranulation of mast cells at the site of previous allergy injections.1 RU has not been described in the setting of peptide-based vaccines. In recent years several immunogenic proteins associated with human malignancies have been identified, allowing the development of antigen-specific cancer vaccines.2 Our group has focused on the HER-2/neu oncoprotein as a tumor antigen. HER-2/neu is a cancer-related protein that is overexpressed in 30% of breast and ovarian cancers. Studies in animal models have demonstrated that HER-2/neu peptide-based vaccines, mixed with GM-CSF as an adjuvant, effectively generate HER2/neu-specific immunity.3 A phase-I trial of HER-2/neu peptide-based vaccines was approved by both the University of Washington Human Subjects Division and the United States Food and Drug Administration. Patients with stable stage III or IV breast, ovarian, or non-small cell lung cancers were vaccinated monthly for 6 months. GM-CSF was used as a vaccine adjuvant. This case report describes 1 patient in whom RU developed 30 days after the last vaccination.

Prognostic significance of HER-2/neu overexpression in stage I adenocarcinoma of lung

Background. Even with early diagnosis and adequate resection, the 5-year survival rate for stage I lung cancer patients is around 60% to 70%. Overexpression of HER-2/neu protein is associated with poor prognosis in lung cancers. In this study, we evaluated the expression of HER-2/neu in cancer cells of lung and assessed their clinicopathologic and prognostic significance. Methods. From 1986 to 1995, clinical data on 42 consecutive patients who underwent complete surgical resection for stage I lung adenocarcinoma were collected. Expression of HER-2/neu in paraffin-embedded tumor samples was determined by immunohistochemistry and scored with a semiquantitative method. Results. Twenty-one of 42 patients were positive for HER-2/neu overexpression in tumor. Compared with patients with low HER-2/neu expression, patients with HER-2/neu overexpression had a significantly higher incidence of early tumor recurrence ( p = 0.014). Survival was also significantly better in patients without HER-2/neu overexpression than in those with HER-2/neu overexpression ( p = 0.0047). By univariate analysis, HER-2/neu overexpression and poor cell differentiation are two important factors correlated with poor prognosis. Conclusions. Expression of HER-2/neu oncoprotein in stage I lung adenocarcinoma can predict the tumor’s aggressiveness. Early tumor recurrence was frequently detected in patients with HER-2/neu overexpression. We recommend an individualized therapeutic strategy based on the level of HER-2/neu oncoprotein in the tumor cells.

The Src Homology 2 and Phosphotyrosine Binding Domains of the ShcC Adaptor Protein Function as Inhibitors of Mitogenic Signaling by the Epidermal Growth Factor Receptor

Upon ligand activation, the epidermal growth factor receptor (EGFR) becomes tyrosine-phosphorylated, thereby recruiting intracellular signaling proteins such as Shc. EGFR binding of Shc proteins results in their tyrosine phosphorylation and subsequent activation of the Ras and Erk pathways. Shc interaction with activated receptor tyrosine kinases is mediated by two distinct phosphotyrosine interaction domains, an NH2-terminal phosphotyrosine binding (PTB) domain and a COOH-terminal Src homology 2 (SH2) domain. The relative importance of these two domains for EGFR binding was examined by determining if expression of the isolated SH2 or PTB domain of ShcC would inhibit EGFR signaling. The SH2 domain potently inhibited numerous aspects of EGFR signaling including activation of Erk2 and the Elk-1 transcription factor as well as EGFR-dependent transformation. Furthermore, the SH2 domain inhibited focus formation by the Neu oncoprotein, another EGFR family member. Surprisingly, inhibition of the EGFR by the SH2 domain did not involve stable association with the receptor. In contrast, the PTB domain associated quite well with the receptor yet had little effect on EGFR signaling. Although the EGFR cytoplasmic tail contains consensus binding sites for the PTB and SH2 domains of ShcC, and both domains of ShcC interact with the receptor in vitro, the SH2 domain is more potent for inhibiting receptor function in vivo. However, inhibition is not due to stable association with the receptor, suggesting that the SH2 domain is binding to a heretofore unknown protein(s) necessary for proper EGFR function.

Epidemiological characteristics and risk factors of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the major cancers in the world. There is a striking variation in HCC incidence rates between various countries, with a highest-to-lowest ratio of 112.5 for males and 54.7 for females. The high-risk populations are clustered in sub-Saharan Africa and eastern Asia. The male-to-female ratio for HCC ranges from < 1 to 6.4 and mostly from 2 to 4. There exist significant variations in the incidence of HCC among different ethnic groups living in the same area and among migrants of the same ethnic groups living in different areas. The age curves of HCC are significantly different in various countries, suggesting variability in exposure to risk factors. Chronic carriers of hepatitis B and C viruses (HBV and HCV, respectively) have an increased risk of HCC. The relative and attributable HCC risk of HBV and HCV carrier status varies in different countries. There exists a synergistic interaction on HCC between the two viruses. Aflatoxin exposure, cigarette smoking, heavy alcohol consumption, low vegetable intake, inorganic arsenic ingestion, radioactive thorium dioxide exposure, iron overload and the use of oral contraceptives and anabolic steroids have been documented as HCC risk factors. Recent molecular epidemiological studies have shown that low serum retinol levels as well as elevated serum levels of testosterone, neu oncoprotein and aflatoxin B1-albumin adduct are associated with an increased HCC risk. There is a synergistic interaction on HCC between chronic HBV infection and aflatoxin exposure. Familial aggregation of HCC exists and a major susceptibility gene of HCC has been hypothesized. Patients of some genetic diseases are at an increased risk of HCC. The genetic polymorphisms of cytochrome P450 2E1 and 2D6 and arylamine N-acetyltransferase 2 are associated with the development of HCC. A dose-response relationship between aflatoxin exposure and HCC has been observed among chronic HBV carriers who have null genotypes of glutathione S-transferase M1 or T1, but not among those who have non-null genotypes. Human hepatocarcinogenesis is a multistage process with the involvement of a multifactorial aetiology. Gene-environment interactions are involved in the development of HCC in humans.

Radioiodinated antibody targeting of the HER-2/ neu oncoprotein

The HER-2/ neu oncogene encodes a 185 kDa phosphoglycoprotein that is overexpressed in breast, ovarian and other cancers. Seven monoclonal antibodies reactive with this oncoprotein were labeled with 131I. In vitro experiments with SKOv3 9002-18 cells determined binding affinity, internalization and degradation. The biodistribution of these antibodies in comparison to 125I-labeled nonspecific antibody was measured in athymic mice with SKOv3 9002-18 ovarian carcinoma xenografts. Antibody 520C9 exhibited the highest and most specific retention in tumor, peaking at 17.4 ± 5.6% ID/ g at 24 h.

Radioiodinated antibody targeting of the HER-2/neu oncoprotein.

The HER-2/neu oncogene encodes a 185 kDa phosphoglycoprotein that is overexpressed in breast, ovarian and other cancers. Seven monoclonal antibodies reactive with oncoprotein were labeled with 131I. In vitro experiments with SKOv3 9002-18 cells determined binding affinity, internalization and degradation. The biodistribution of these antibodies in comparison to 125I-labeled nonspecific antibody was measured in athymic mice with SKOv3 9002-18 ovarian carcinoma xenografts. Antibody 520C9 exhibited the highest and most specific retention in tumor, peaking at 17.4 +/- 5.6% ID/g at 24 h.