UNIPROT:P04626 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the multistep progressive pathogenesis of human breast cancer, comedo ductal carcinoma in situ (DCIS) represents a preinvasive precursor lesion for therapy resistant invasive cancer. Human tissue derived cell culture models exhibiting molecular similarities to clinical DCIS facilitate an important preclinical mechanistic approach for evaluation of preventive efficacy of natural and synthetic chemopreventive compounds. Natural phytochemicals present in fresh fruits, vegetables and grain products are likely to offer protection against cancer. The clinical efficacy of these natural phytochemicals, however, depends on extrapolation, and is therefore equivocal. The present study determined whether the natural soy isoflavone genistein (GEN) inhibited aberrant proliferation in 184-B5/HER cells (a model for human comedo DCIS) and identified possible mechanisms responsible for its efficacy. Human reduction mammoplasty derived HER-2/neu oncogene expressing preneoplastic 184-B5/HER cells represented the experimental system. Flow cytometry and cellular epifluorescence based assays were utilized to quantitate the alterations in cell cycle progression, cellular apoptosis, and in the status of cell cycle regulatory and apoptosis-associated gene product expression. The 184-B5/HER cells exhibited specific immunofluorescence to p185HER, p53, EGFR, but not to ERalpha, thus resembling comedo DCIS. Treatment of 184-B5/HER cells with GEN resulted in a dose-dependent decrease in the viable cell population, increase in the G0/G1:S + G2/M ratio and enhancement of sub G0/G1 (apoptotic population). Exposure to the maximum cytostatic 10 microM dose of GEN down-regulated HER-2/neu mediated signal transduction as evidenced by a 73.9% decrease (p=0.001) in p185HER specific, and a 89.8% decrease (p=0.001) in phosphotyrosine specific immunofluorescence. The increase in G0/G1:S + G2/M ratio in response to the treatment with 10 microM GEN was associated with a 85.5% decrease (p=0.001) in immunoreactivity to PCNA and a 128.6% increase (p=0.004) in immunoreactivity to the cyclin dependent kinase inhibitor p16INK4. The induction of apoptosis by GEN was associated with a 52.8% decrease (p=0.001) in the immunoreactivity to antiapoptotic Bcl-2 and with a 195.9% (p=0.001) increase in the immunoreactivity to proapoptotic Bax. Thus, preventive efficacy of GEN in HER-2/neu+/ER- 184-B5/HER cells may be due to its ability to down-regulate HER-2/neu mediated signal transduction, increase the expression of the cyclin dependent kinase inhibitor p16INK4, and induce Bcl-2 dependent apoptosis. These data provide evidence that GEN may be a potential chemopreventive lead compound for human comedo DCIS. The 184-B5/HER cells, may therefore, provide a high throughput mechanistic bioassay to identify new chemopreventive agents for human breast cancer.
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PMID:Soy isoflavone genistein modulates cell cycle progression and induces apoptosis in HER-2/neu oncogene expressing human breast epithelial cells. 1223 20

Breast cysts are associated with an increased risk of breast cancer. Some biomarkers such as estrogen receptor alpha (ERa), progesterone receptor (PR), and cyclin D1, show similar patterns of expression in epithelial cells lining breast cysts as malignant epithelial cells in local and invasive ductal breast cancer. We have attempted to answer two questions: (1) Do epithelial cells lining breast microcysts (cysts which can only be seen with a microscope) express biomarkers in a similar pattern to breast ductal carcinoma in situ and invasive ductal carcinoma? (2) Are breast microcysts precursors of breast cancer or are they part of normal involution of the breast? Seventy two archival open breast biopsy specimens of ductal carcinoma in situ and invasive ductal carcinoma and 32 normal breast biopsies from Australian women who had breast reduction surgery were selected from hospital archives. All specimens were analysed by standard immunohistochemistry for ERa, PR, cyclin D1, bcl-2, p53 and erbB-2 expression. In the same specimens, the pattern of high biomarker expression was very similar for all the above biomarkers in epithelial cells lining microcysts and in both ductal carcinoma in situ and invasive ductal carcinoma c. ErbB-2 was not expressed in normal control specimens. ErbB-2 was expressed in the same specimens in an increasing proportion of normal breast acini, microcysts and cancer cells in 36% of specimens with breast cancer. An apparent progression was observed from normal breast acini, to proliferation of epithelial cells in microcysts, ductal carcinoma in situ and invasive ductal carcinoma in the same specimen. When these findings are considered with other reports we conclude: (1) that epithelial cells lining breast cysts highly express biomarkers in a similar pattern to ductal carcinoma in situ and invasive ductal carcinoma; (2) that some microcysts are not part of normal involution of the breast and in some women may be part of the transition from normal to cancer.
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PMID:Microcysts and breast cancer: a study of biological markers in archival biopsy material. 1235 10

We reviewed 10 cases of pleomorphic lobular (ductal lobular) carcinoma in situ (PL/DLCIS) of the breast and compared them with 14 cases of pleomorphic lobular carcinoma in situ (PLCIS) found in association with invasive pleomorphic lobular carcinoma. The histologic features; immunohistochemical staining for estrogen receptors (ERs), p53, Ki67, E-cadherin, and gross cystic disease fluid protein-15 (GCDFP-15); and results of fluorescence in situ hybridization for HER-2/neu gene amplification were evaluated in all 24 cases. Histologically, PL/DLCIS cells were similar to those of PLCIS with invasion in that they were discohesive and medium to large in size with moderate to marked nuclear pleomorphism, small to prominent nucleoli, and moderate to abundant eosinophilic or vacuolated cytoplasm. In both groups, central necrosis was present in a small number of cases, and classic LCIS coexisted with the in situ lesion in less than half of the cases; in situ carcinomas were positive for ERs in 23 (100%) of 23 cases, p53 in 6 (25%) of 24 cases, and GCDFP-15 in 14 (74%) of 19 cases. The percentage of Ki67-positive tumor nuclei indicated moderate to high (more than 20%) proliferative activity in 8 (47%) of 17 cases. Immunostaining for E-cadherin was negative in all 24 cases. HER-2/neu gene amplification was observed in 1 (4%) of 23 cases. In cases with associated invasion, PLCIS had cytologic features and immunostaining patterns similar to those of the invasive pleomorphic component. Seven of the 10 patients who had PL/DLCIS without invasion underwent lumpectomy or simple mastectomy. Six of these patients had no evidence of disease in follow-up periods ranging from 4 to 32 months; the seventh patient developed recurrent disease 12 months after undergoing lumpectomy. We conclude that the cytologic features and biomarker expression profile of PL/DLCIS are similar to those of PLCIS with invasion but somewhat different from those of classic LCIS and ductal carcinoma in situ. Long-term follow-up studies are needed to further define the natural history of PL/DLCIS and its optimal management.
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PMID:Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases. 1237 50

HER-2/neu overexpression occurs in a proportion of invasive breast carcinomasand is an adverse prognostic indicator, although its apparent strength as a prognostic indicator varies in different studies. Paradoxically, HER-2/neu is overexpressed with particularly high frequency in ductal carcinoma in situ (DCIS). We have hypothesized and presented supporting data that HER-2/neu is actively signaling in a subset of the tumors in which it is overexpressed. We use an activation state-dependent anti-HER-2/neu monoclonal antibody (PN2A) produced in our laboratory to study this paradigm immunohistochemically. In this report, we analyze the characteristics of 219 cases of DCIS with respect to HER-2/neu expression and activation state. We find that 58% of cases of DCIS with overexpression have the receptor in the activated state, a substantially greater proportion than we have previously noted for invasive carcinomas. Although HER-2/neu overexpression in general was inversely correlated with hormone receptor expression, cases with activated HER-2/neu had the lowest hormone receptor positivity rate. Statistically significant correlations with activated HER-2/neu were not noted for tumor size, presence of calcifications, necrosis or fibrosis, or indicators of angiogenesis. These results suggest that examination of activated HER-2/neu status may better reflect the biology of a tumor than overall determination of HER-2/neu levels. Our finding that active signaling by HER-2/neu, as detected by this assay, is more frequent in DCIS than previously noted for invasive carcinoma implicates signaling by HER-2/neu as having a critical role in the early stages of breast tumorigenesis.
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PMID:Active signaling by HER-2/neu in a subpopulation of HER-2/neu-overexpressing ductal carcinoma in situ: clinicopathological correlates. 1243 65

The hypothetical multistep model of breast carcinogenesis suggests a transition from normal epithelium to invasive carcinoma via intraductal hyperplasia (without and with atypia) and in situ carcinoma. These presumptive precursor lesions are currently defined by their histological features, and their prognosis is imprecisely estimated from indirect epidemiological evidence. Cytogenetic and molecular-genetic analysis of these lesions give evidence for an accumulation of various genetic alterations during breast tumorigenesis. Using immuno-histochemistry overexpression of the c-erbB-2 oncogene was found in ductal carcinoma in situ (DCIS), but not in atypical intraductal hyperplasia (AIDH) and intraductal hyperplasia (IDH). An expression of mutant p53 tumor suppressor gene as well as expression of cyclin D1 was identified in DCIS. In IDH lesions loss of heterozygosity (LOH) at various loci could be identified, and comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) studies delivered evidence for DNA amplification on chromosomal region 20q13 in the early stage of IDH.However, little is currently known about genetic alterations in those premalignant lesions, and the chronology of genetic alterations and histopathological changes during carcinogenesis is mainly undiscovered.
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PMID:Genetic alterations in presumptive precursor lesions of breast carcinomas. 1244 56

A subset of breast carcinomas shows unexplained overexpression of HER-2/neu protein without HER-2/neu gene amplification. These tumors are often scored 2+ by immunohistochemistry (DAKO HercepTest). In vitro, Zonula occludens-1 (ZO-1), a tight junction protein, can upregulate HER-2/neu expression by sequestering a repressor of the HER-2/neu gene promoter. To assess this relation in vivo, we examined the expression of ZO-1 in 2 series of breast carcinomas. In group 1, 35 invasive breast carcinomas previously scored by HercepTest for HER-2/neu status (negative [n = 12], 2+ [n = 13], 3+ [n = 10]) were examined by immunohistochemistry for expression of ZO-1. ZO-1 expression was then correlated with HER-2/neu expression status. Twenty-four of 35 carcinomas (69%) were positive for ZO-1 expression. Frequency of ZO-1 expression did not differ between HER-2/neu-negative carcinomas (67%) and 2+ positive carcinomas (77%). Carcinomas with 3+ HER-2/neu expression were less commonly positive for ZO-1 (60%), but this difference was not significant. Twenty tumors contained ductal carcinoma in situ (DCIS); 18 of 20 DCIS (90%) were positive for ZO-1. Interestingly, in those tumors with ZO-1-positive DCIS, 4 of 18 (22%) were negative for ZO-1 expression in the invasive tumor. In group 2, 31 of 42 (74%) fluorescent in situ hybridization-nonamplified breast carcinomas showed ZO-1 expression, also with no significant difference in frequency between HER-2/neu-positive (by immunohistochemistry) and negative cases. ZO-1 expression does not correlate with HER-2/neu expression in breast carcinomas. Other causes of HER-2/neu protein overexpression should be sought in cases without HER-2/neu gene amplification.
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PMID:Zonula occludens-1 and Her-2/neu expression in invasive breast carcinoma. 1277 95

Abnormalities in G1/S transition in cell cultures have been attributed to alterations in ErbB (erythroblastic leukaemia viral [v-erb-b] oncogene homologue, avian) signalling, cyclin D1 overexpression or disturbance of the p21(WAF1) (p21)-mediated cell cycle arrest induced by p53. To investigate the significance of these mechanisms on an early stage of human breast tumour growth, we studied the expression of EGFR (ErbB1), HER-2/neu (ErbB2), cyclin D1, p21 and p53 as well as oestrogen (ER) and progesterone receptor (PgR) in paraffin sections of 45 ductal carcinoma in situ (DCIS) by immunohistochemistry. Cell proliferation was assessed by immunohistochemical quantification of Ki-67. Five cases with cyclin D1 overexpression were analysed by FISH for CCND1 amplification. Increased proliferative activity was observed in 46% of DCIS. It was correlated with the expression of EGFR and HER-2/neu (p < 0.05), but neither with cyclin D1 and p21 overexpression nor with p53 accumulation. ErbB positive status was associated with p21 overexpression (p < 0.05). In addition we found a correlation between the overexpression of p21 and cyclin D1 restricted to ErbB-positive cases (p = 0.013). ErbB-negative tumours with increased proliferative activity were ER and cyclin D1 positive. No CCND1 amplification was detected in the analysed cases. In conclusion, our data support that EGFR and HER-2/neu play an important role in cell cycle control in DCIS. p21 appears to be a potential mediator of ErbB signalling. We propose that cyclin D1 could be indirectly induced by ErbB signalling through p21. Besides, ER-mediated upregulation of cyclin D1 seems to be a possible mechanism of maintaining cell proliferation in DCIS in case of EGFR- and HER-2/neu-negativity.
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PMID:EGFR, HER-2/neu, cyclin D1, p21 and p53 in correlation to cell proliferation and steroid hormone receptor status in ductal carcinoma in situ of the breast. 1282 53

Carcinoma in situ of the breast (CIS) comprise a heterogenous group of lesions, covering a wide spectrum of clinical conditions and histopathological changes. With respect to biological behavior, CIS range from biologically aggressive lesions with a substantial risk of progression into invasive carcinoma (IC), to lesions with a very low malignant potential. Two main types of CIS are described--ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). Previous studies of CIS indicate that approximately a third will subsequently develop IC. Autopsy studies indicate that CIS is frequently occurring and it was estimated that about 20% of all women will develop CIS during lifetime. Only a minor fraction is ever diagnosed, although the incidence of DCIS is increasing, especially related to mammography screening. The lack of knowledge about the biological significance of the histopathological subtypes was the background of the present study. In 1982, a nationwide, prospective study of CIS (protocol DBCG 82-IS) was initiated by the Danish Breast Cancer Cooperative Group (DBCG). From this protocol, the group of patients treated with breast conservation surgery (BCS) constituted the material for clinico-histological investigation. A total of 275 women were included in the period 1982-89. Follow-up studies showed that recurrence rate was significantly related to nuclear size of the primary lesion. Since nuclear changes might be related to DNA content and, furthermore, many invasive breast carcinomas were shown to be DNA aneuploid, flow cytometric (FCM) DNA ploidy analysis was performed in a series of DCIS lesions. More than 80% of these lesions were DNA aneuploid, with a distribution similar to that found in invasive carcinomas. This finding raised the hypothesis that the DNA pattern of an invasive carcinoma was already established at the preinvasive stage of DCIS. Therefore, FCM DNA analysis was performed on a series of ICs with predominance of DCIS. Partial or complete concordance in DNA ploidy between DCIS and IC within the individual case was found in most cases, except for the additional presence in the IC component of DNA hyperdiploid clones that might possibly be of importance for the process of invasion. In order to further characterize CIS lesions and, possibly, to discriminate biologically different groups, immunohistochemical markers were investigated in a consecutive series of CIS and IC with predominance of DCIS. The results were correlated to the histopathological and DNA ploidy findings. In DCIS, significant correlation was shown between large nuclear size and comedonecrosis, both of which showed also strong association to DNA aneuploidy, high proliferation activity, low steroid receptor content, and overexpression of c-erbB-2 and p53--factors that may indicate an aggressive behavior. Small nuclear CIS, whether LCIS or DCIS, on the contrary, were DNA diploid with low proliferation, and no cases showed overexpression of c-erbB-2 and p53. In IC, comparison of the DCIS and the invasive component showed similar patterns. No significant differences, in neither morphology, immunohistochemistry, nor DNA ploidy, were shown between DCIS without and with invasion. These findings may indicate that none of the parameters in question may on its own be essential for the decisive event of invasive growth.
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PMID:Carcinoma in situ of the female breast. A clinico-pathological, immunohistological, and DNA ploidy study. 1287 68

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. In this review, the association of HER-2/neu gene and protein abnormalities with prognosis and response to therapy with trastuzumab and to other therapies in breast cancer is presented. By considering a series of 80 published studies encompassing more than 25,000 patients, the relative advantages and disadvantages of Southern blotting, polymerase chain reaction amplification, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The role of HER-2/neu testing for the prediction of response to trastuzumab therapy in breast cancer is presented as well as its potential impact on responses to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review also evaluates the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response.
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PMID:The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. 2696 27

PC-cell-derived growth factor (PCDGF, progranulin) is a novel autocrine growth factor that is overexpressed in human breast cancer cell lines. We have examined immunohistochemical PCDGF expression in 206 paraffin-embedded human breast lesions and investigated its association with clinicopathological variables. PCDGF staining was observed in breast carcinoma, whereas it was almost always negative in benign breast epithelium. PCDGF expression was more common in invasive ductal carcinoma (80% cases positive) than in invasive lobular carcinoma (53% positive). PCDGF staining was almost never observed in lobular carcinoma in situ. Ductal carcinoma in situ expressed PCDGF in 66% of the cases, and this expression correlated strongly with nuclear grade. Similar correlation was observed between PCDGF expression and histologic grade of invasive ductal carcinoma. Average Ki-67 index of PCDGF-negative/weakly positive invasive carcinomas (30.3) was significantly lower than that of strongly PCDGF-positive tumors (48.8, P=0.01). A larger percentage of tumors that expressed PCDGF with a staining intensity of 2+ or 3+ were p53 positive (44%) than were PCDGF-negative tumors (25%), P=0.02. PCDGF expression was independent of c-erbB-2 overexpression and of ER and PR status. Our study provides the first evidence of high incidence of PCDGF expression in human breast cancer in which it correlates with clinicopathological variables such as tumor grade, proliferation index, and p53 expression. These characteristics, as well as the virtual absence of expression in benign breast tissue, suggest an important role of PCDGF in breast cancer pathogenesis and make it a potential novel target for the treatment of breast cancer.
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PMID:Expression of PC-cell-derived growth factor in benign and malignant human breast epithelium. 1465 16

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