Close association between HER-2 amplification and overexpression in human tumors of non-breast origin

Tapia, Coya; Glatz, Katharina; Novotny, Hedvika; Lugli, Alessandro; Horcic, Milo; Seemayer, Christian A.; Tornillo, Luigi; Terracciano, Luigi; Spichtin, Hanspeter; Mirlacher, Martina; Simon, Ronald; Sauter, Guido

doi:10.1038/modpathol.3800729

Cited by 59 publications

(54 citation statements)

References 37 publications

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“…The rate of ErbB2 overexpression/amplification in these cancers has been reported at approximately 20-25%, depending on the method of evaluation and the definition used. [11][12][13][14][15] In terms of the relatively high rate of chemotherapy resistance in oesophageal adenocarcinomas, 16,17 additional therapeutic options, such as ErbB2-targeting are of high demand for patients with advanced or metastatic disease.…”

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confidence: 99%

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

et al. 2011

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Amplification and overexpression of ErbB2 (Her2) is a frequent event in oesophageal adenocarcinomas. Assessment of ErbB2 status is crucial for identifying patients who are likely to benefit from treatment with trastuzumab. In this study, we performed a comprehensive analysis of ErbB2 amplification and expression in 142 oesophageal adenocarcinomas by comparing the most commonly used methods for ErbB2 assessment: ErbB2 expression was determined by immunohistochemistry and was scored (0, 1 þ , 2 þ and 3 þ ) according to a recently described modified scoring system for gastric cancer. ErbB2 amplification was evaluated by bright field double in situ hybridisation. The results were compared with pathologic features, patients' survival and previously published data from fluorescence in situ hybridisation analysis. On the basis of immunohistochemistry, which was applicable in 110 cores of the cases, 83 tumours (75%) had a score of 0 or 1 þ (immunohistochemistry negative), 13 tumours (12%) were scored as 2 þ and 14 tumours (13%) were scored as 3 þ . In situ hybridisation data were obtained from 142 cases. There was a highly significant correlation of immunohistochemistry, bright field in situ hybridisation and fluorescent in situ hybridisation (Po0.001 each). In total, 41 tumours (29%) were categorised as ErbB2 positive, which was defined as immunohistochemistry 3 þ and/or an ErbB2/Chr17 quotient of Z2 as assessed by either bright field double in situ hybridisation or fluorescence in situ hybridisation. ErbB2 positivity was observed more frequently in tumours with lower differentiation grades (P ¼ 0.029). Patients with ErbB2-positive tumours had a significantly worse prognosis, both in univariate analysis (P ¼ 0.004) and in multivariate analysis (P ¼ 0.03).In conclusion, we demonstrate that a significant number of oesophageal adenocarcinomas are positive for ErbB2. Assessment of ErbB2 amplification can be equivalently performed by conventional fluorescence in situ hybridisation or other lightmicroscopy-based methods, such as the novel bright field double in situ hybridisation technique. Modern Pathology (2011) 24, 908-916;

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confidence: 99%

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

et al. 2011

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“…Besides its crucial roles in normal cells, Her2/neu has been found to be amplified and/or overexpressed in several types of cancer inducing tumor growth (3). Her2/neu overexpression is associated with a poor prognosis for breast, gastric, and ovarian cancer (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Falahi

Huisman

Kazemier

et al. 2013

Molecular Cancer Research

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The human epidermal growth factor receptor-2 (HER2/neu/ERBB2) is overexpressed in several cancer types. Although therapies targeting the HER2/neu protein result in inhibition of cell proliferation, the anticancer effect might be further optimized by limiting HER2/neu expression at the DNA level. Towards this aim, epigenetic editing was performed to suppress HER2/neu expression by inducing epigenetic silencing marks on the HER2/neu promoter.HER2/neu expression and HER2/neu promoter epigenetic modification status were determined in a panel of ovarian and breast cancer cell lines. HER2/neu-overexpressing cancer cells were transduced to express a zinc finger protein (ZFP), targeting the HER2/neu gene, fused to histone methyltransferases (G9a, SUV39-H1)/super KRAB domain (SKD). Epigenetic assessment of the HER2/neu promoter showed that HER2/neu-ZFP fused to G9a efficiently induced the intended silencing histone methylation mark (H3K9me2). Importantly, H3K9me2 induction was associated with a dramatic downregulation of HER2/neu expression in HER2/neu-overexpressing cells. Downregulation by SKD, traditionally considered transient in nature, was associated with removal of the histone acetylation mark (H3ac). The downregulation of HER2/neu by induced H3K9 methylation and/or reduced H3 acetylation was sufficient to effectively inhibit cellular metabolic activity and clonogenicity. Furthermore, genome-wide analysis indicated preferential binding of the ZFP to its target sequence. These results not only show that H3K9 methylation can be induced but also that this epigenetic mark was instructive in promoting downregulation of HER2/neu expression.

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“…The authors believe that an immunohistochemistry technique performed by a skilful pathologist and reviewed by a second one is a reliable method for oncogene expression analyses. Recently, a paper showed close association between Her-2/neu amplification and overexpression in human tumours of non-breast origin 12 which further corroborates immunohistochemistry reliability. Even though, many immunohistochemical cerbB-2 papers show results using the herceptest score, a reliable comparison seems to be difficult because usually how scores were determined have not been clearly specified.…”

Section: Results Results Results Resultsmentioning

confidence: 56%

“…There is a wide variability of their expression worldwide ranging from 8% and 62% for Her-2/Neu. Recently a study from Switzerland reported 4.9% her-2/ neu positivity by immunohistochemistry 12 . Until the writing of the present manuscript the authors were unaware of or were able to retrieve any similar studies involving brazilian populations at risk for gastric cancer.…”

Section: Results Results Results Resultsmentioning

confidence: 99%

“…In a randomized clinical trial with 469 patients with metastatic breast cancer positive to HER-2 overexpression a 50% overall response rate was observed for patients assigned to trastuzumab plus chemotherapy treatment arm as compared with 35% for those allocated to the chemotherapy arm only; and the median survival Recently, trastuzumab was shown to be effective as adjuvant therapy in Her-2 positive breast cancer patients too 12 . Trastuzumab showed good response of HER-2+ pancreatic cell lines in an experimental study 15 .…”

Section: Results Results Results Resultsmentioning

confidence: 99%

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Immunohistochemical expression of HER-2/NEU-CERBB-2 in patients with adenocarcinoma of the stomach

Cirne-Lima¹,

Rosa²,

Kulczynski³

et al. 2009

Rev. Col. Bras. Cir.

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OBJECTIVES: To determine the prevalence of Her-2/Neu-cerbb-2 in the gastric mucosa of patients with gastric adenocarcinoma in a brazilian patient group. METHODS: The immunohistochemical expression of Her-2/Neu was studied in 37 formalin-fixed paraffin-embedded tissue sections. RESULTS: The immunohistochemical reaction produced by the anti-HER-2/Neu antibody was positive in two cases (5.4%). CONCLUSION: The low prevalence of Her-2/Neu observed in these southern brazilian cases is probably due to the great number of poorly differentiated cancers in this serie.

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Close association between HER-2 amplification and overexpression in human tumors of non-breast origin

Cited by 59 publications

References 37 publications

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Immunohistochemical expression of HER-2/NEU-CERBB-2 in patients with adenocarcinoma of the stomach

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