• The Korean Journal of Physiology and Pharmacology
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• v.4 no.6
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• pp.507-513
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• 2000

ErbB3/HER3 is a cell surface receptor which belongs to the ErbB/HER subfamily of receptor protein tyrosine kinases. When expressed in NIH/3T3 cells, ErbB3 can form heterodimeric coreceptor with endogenous ErbB2. Among known intracellular effectors of the ErbB2/ErbB3 are mitogen-activated protein kinase (MAPK) and phosphoinositide (PI) 3-kinase. In the present study, we studied relative contributions of above two distinct signaling pathways to the heregulin-induced mitogenic response via activated ErbB3. For this, clonal NIH-3T3 cell lines expressing wild-type ErbB3 and ErbB3 mutants were stimulated with $heregulin{\beta}_1$. While cyclin D1 level was markedly high and further increased by treatment of heregulin in cells expressing wild-type ErbB3, the elimination of either Shc binding or PI 3-kinase binding lowered both levels. This result was supported by the reduction of cyclin $D_1$ expression by preteatment with MAPK kinase inhibitor or PI 3-kinase inhibitor before stimulation with heregulin. In accordance with the cyclin $D_1$ expression, elimination of either Shc binding or PI 3-kinase binding reduced the heregulin-induced DNA synthesis and cell growth rate. Our results obtained by the comparison of wild-type and ErbB3 mutants indicate that the full induction of the cell cycle progression through $G_1/S$ phase by ErbB3 activation is dependent on both Shc/MAPK and PI 3-kinase signal transduction pathways.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1333-1337
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• 2014

Background: Astrocytic tumors, the most common primary glial tumors of the central nervous system, are classified from low to high grade according to the degree of anaplasia and presence of necrosis. Despite advances in therapeutic management of high grade astrocytic tumors, prognosis remains poor. In the present study, the frequency and prognostic significance of c-erb-B2 in astrocytic tumors was investigated. Materials and Methods: Records of 72 patients with low- and high-grade astrocytic tumors were evaluated. The expression of C-erbB-2 was determined immunohistochemically and intensity was recorded as 0 to 3+. Tumors with weak staining (1+) or no staining (0) were considered Her-2 negative, while tumors with moderate (2+) and strong (3+) staining were considered Her-2 positive. Results: Of the 72 patients, 41 (56.9%) had glioblastoma (GBM), 10 (13.9%) had diffuse astrocytoma, 15 (20.8%) had anaplastic astrocytoma, 6 (8.3%) had pilocytic astrocytoma. C-erbB-2 overexpression was detected in the tumor specimens of 17 patients (23.6%). Six (8.3%) tumors, all GBMs, exhibited strong staining, 2 (2.7%) specimens, both GBMs, exhibited moderate staining, and 9 specimens, 5 of them GBMs (12.5%), exhibited weak staining. No staining was observed in diffuse astrocytoma and pilocytic astrocytoma specimens. Median overall survival of patients with C-erbB-2 negative and C-erbB-2 positive tumors were 30 months (95%CI: 22.5-37.4 months) and 16.9 months (95%CI: 4.3-29.5 months), respectively (p=0.244). Conclusions: Although there was no difference in survival, C-erbB-2 overexpression was observed only in the GBM subtype.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.1
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• pp.249-254
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• 2016

Molecular detection methods such as RT-PCR for detecting breast cancer-associated gene expression in the peripheral blood have the potential to modify breast cancer (BC) staging and therapy. In this regard, we evaluated the potential of erb-B2 molecular marker in BC detection and analyzed the expression of erb-B2 mRNA in the peripheral blood and fresh tissue samples of 50 pretreated female BC patients and 50 healthy females by reverse transcription-PCR (RT-PCR) method. We also assessed the correlation of erb-B2 mRNA marker positivity in peripheral blood and tumor tissue samples with clinical and pathological factors in BC patients in order to evaluate its prognostic value. It was shown that there is a significant difference between healthy females and BC patients with expression of the erb-B2 molecular marker (p<0.01). A significant difference between the expression of erb-B2 in the peripheral blood and tissue samples of BC patients (p<0.01) and the frequency of circulating erb-B2 mRNA expression in peripheral blood and in tissue was detected by RT-PCR. No correlation was found between erb-B2 mRNA expression in blood or tumor tissue samples and lymph node, tumor grade, tumor stage, tumor size, patient's age, ki67, estrogen receptor (ER), progesterone receptor (PGR), P53, and HER-2 status. However, in a small subset of 31 BC patients we found that expression of erb-B2 in peripheral blood or in both peripheral blood and tumor tissue was directly correlated with lympho-vascular invasion and perineural invasion as poor prognostic features. The highest rates of erb-B2 expression in peripheral blood or tumor tissue were in the ER and PR negative and HER-2 positive group. This study suggests that the application of the RT-PCR and immunohistochemical methods for erb-B2 molecular marker detection would provide a higher detection rate, especially in early stage BC.

• BMB Reports
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• v.49 no.12
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• pp.651-652
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• 2016

EphA2 has been implicated in amplifying ErbB2 tumorigenic signaling. One protein that interacts with EphA2 is the Anks1a PTB adaptor. However, the precise role of Anks1a in EphA2-mediated tumorigenesis is unclear. We demonstrated that Anks1a localizes to the ER upon phosphorylation and that the Ankyrin repeats and PTB of Anks1a bind to EphA2 and Sec23, respectively. Thus, Anks1a facilitates the selective packaging of EphA2 into COPII vesicles. Additionally, Anks1a knockout mice, a phenocopy of EphA2 knockout mice, exhibited markedly reduced ErbB2-induced breast tumorigenesis. Strikingly, ErbB2 did not localize to the cell surface following Anks1a knockdown in primary mammary tumor cells over-expressing ErbB2. Importantly, EphA2 was critical for stabilizing ErbB2 through complex formation, but its interaction with Anks1a also facilitated ErbB2 loading into COPII carriers. These findings suggest a novel role for Anks1a in the molecular pathogenesis of breast tumors and possibly other human diseases.

• Proceedings of the Korean Society of Veterinary Pathology Conference
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• 2003.10a
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• pp.40-40
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• 2003

The c-erbB2/neu oncogene (alias HER2, NEU) encoding a tyrosine kinase receptor protein, the overexpression of which correlates with a more rapid progression and a worse prognosis in human breast cancer [1]. Otherwise, this gene is still poorly investigated in veterinary oncology [2,3]. To gain insight into the patterns of c-erbB2/neu status in canine mammary tumor, we constructed one such mammary tumor tissue microarray (TMA) from 60 tumors from our lab. This enabled the amplification of c-erbB2/neu oncogene of all 60 tumors to be simultaneously analyzed by chromogenic in situ hybridization (CISH). The aim of this study was to evaluate status of c-erbB2/neu oncogene in canine mammary tumors and to correlate this status with the differentiation grade of neoplasm. (omitted)

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.6947-6951
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• 2015

Background: Oral carcinoma (OC) remains one of the most difficult malignancies to cure. Hesa-A is an Iranian herbal-marine compound that has shown promising anti-tumor properties against various human tumors. However, its mechanism of action remains to be addressed. The present study was conducted to evaluate the effect of two doses of Hesa-A on mRNA expression of erb$\backslash$b2 as a main prognosticator tumor marker for OC in an animal model. Materials and Methods: A total of 60 rats were randomly divided into 5 groups of 12 animals each. Rats in carcinoma groups received 0, 250 and 500mg/kg body weight doses of Hesa-A 3 times a day. The other two groups were considered as treated and untreated control groups. At the end of the experiment, animals were sacrificed and tongue tissues subjected to H and E staining and real time PCR. Results: Our results showed that compared to the control group, erb$\backslash$b2 was over-expressed ~ 30% in the carcinoma group. After treatment with 250mg/kg and 500mg/kg body weight of Hesa-A, erb$\backslash$b2 levels dropped by 24.1% and 3.4 % respectively compared to the control carcinoma group (p<0.01, p<0.0001). Moreover, there was a significant relation between erb$\backslash$b2 mRNA content and observed pathological changes in studied groups (p<0.05). Conclusions: These data provide insight into mechanism(s) by which Hesa-A may improve clinical outcome of oral carcinoma by affecting oncogene erb$\backslash$b2 expression and suggest Hesa-A as an effective chemotherapeutic agent in treatment of HER+tumors.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5709-5714
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• 2014

Background: An association between alcohol/tobacco use and risk of metastasis in breast cancer has been clearly shown. Materials and Methods: The present study explored, in 48 samples of tissue from mammary ductal carcinoma (taken from Mexican women with an average age of $58.2{\pm}10.9$ years), the association of risk of metastasis with the status of hormonal receptors and the c-erbB2 protein (by immunohistochemistry) as well as clinical, histopathological and sociodemographic factors. Results: Of 48 patients, 41.6% (20/48) presented with metastasis, 43.8% were positive for the estrogen receptor (RE+), 31.3% for the progesterone receptor (RP+) and 47.7% for c-erbB2 (c-erbB2+). The following combinations were found: RE+/RP+/c-erbB2+ 8.3%, RE+/RP+ 22.9%, RE+/RP- 20.8%, RE-/RP+ 8.3%, RE-/RP-/c-erbB2- 22.9% and RE-/RP- 47.8%. There were 12 patients who used alcohol/tobacco, of which 91.6% did not present metastasis and 81.9% were RE-/RP-. Compared to the RE-/RP-/c-erbB2+, the RE+/RP+/c-erbB2+ group had a 15-fold greater risk for metastasis (95%CI, 0.9-228.8, p=0.05). The carriers of the double negative hormonal receptors had a 4.7 fold greater probability of being (or having been) smokers or drinkers (95%CI, 1.0-20.4, p = 0.03). Conclusions: There was a clear protective effect of using alcohol and/or tobacco, in the cases included in the present study of mammary ductal carcinoma, associated with double negative hormonal receptors. However, this association could be due to a protective factor not measured (Neyman bias) or to a bias inherent in the rate of hospitalization (Berkson fallacy). This question should be explored in a broad prospective longitudinal study.

• Korean Journal of Head & Neck Oncology
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• v.29 no.1
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• pp.1-10
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• 2013

연구배경 및 목적 표피성장인자수용체(EGFR)는 HER2/neu(erbB2), HER3(erbB3), HER4(erbB4)를 포함하는 receptor tyrosine ki-nase의 erbB 그룹에 속하는 수용체이다. 표피성장인자수용체의 과발현은 다양한 종류의 암, 특히 두경부편평세포암에서 예후를 악화시킨다고 알려져 있다. 이에 저자들은 하인두편평세포암에서 표피성장인자수용체의 발현 및 분포를 확인하고, 하인두암에서 표피성장인자(EGF)가 암세포의 증식과 침습에 미치는 영향에 대해 알아보고자 하였다. 대상 및 방법 57명의 하인두편평세포암 환자의 조직에서 표피성장인자수용체의 발현을 면역화학적염색을 통해 확인하고, 이에 대해 임상병리학적 요인과 생존율에 대한 분석을 시행하고, 일부 환자의 정상 및 암조직에서 Western blot을 시행하였다. 하인두편평세포암 세포주인 FaDu에서 proliferative assay, colony dispersion, wound healing assay, invasion assay를 시행하여, 하인두암의 진행에서 표피성장인자의 역할에 대하여 분석하였다. 또한 RT-PCR과 Zymography를 통하여 Matrix metalloproteinase(MMP)-2, 9의 발현을 확인하였다. 결 과 63.2%의 하인두편평세포암 조직에서 표피성장인자수용체의 발현이 확인되었다. 표피성장인자수용체의 발현은 정상조직에서 비하여 하인두암 조직에서 유의하게 증가되어 있었으며, 병리학적 병기(p=0.022)가 올라갈수록 유의하게 증가하였으나, 증례수의 제한으로 생존율에서는 통계적 유의성을 얻지는 못했다(p=0.053). in vitro의 결과로 표피성장인자를 FaDu 세포주에 처리하였을 때, FaDu 세포주의 증식이 유의하게 증가되었으며(p<0.05), Transwell invasion chamber상 침습의 증가가 확인되었다(p<0.05). RT-PCR과 zymogram 실험상 표피성장인자처리시 FaDu 세포주의 MMP-2, 9이 발현이 증가되고 활성화되는 것이 확인하였다. 결 론 본 연구에서 표피성장인자수용체의 과발현이 하인두암의 예후 인자로서의 가능성을 확인하였고, 표피성장인자가 하인두편평세포암의 증식과 침습에 관여하는 것을 확인하였다.

• Radiation Oncology Journal
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• v.34 no.1
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• pp.1-9
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• 2016

Overexpression of human epidermal growth factor receptor 2 (HER2) is found in about 20% of breast cancer patients. With treatment using trastuzumab, an anti-HER2 monoclonal antibody, systemic control is improved. Nonetheless, the incidence of brain metastasis does not be improved, rather seems to be increased in HER2-positive breast cancer. The mainstay treatment for brain metastases is radiotherapy. According to the number of metastatic lesions and performance status of patients, radiosurgery or whole brain radiotherapy can be performed. The concurrent use of a radiosensitizer further improves intracranial control. Due to its large molecular weight, trastuzumab has a limited ability to cross the blood-brain barrier. However, small tyrosine kinase inhibitors such as lapatinib, has been noted to be a promising agent that can be used as a radiosensitizer to affect HER2-positive breast cancer. This review will outline general management of brain metastases and will focus on preclinical findings regarding the radiosensitizing effect of small molecule HER2 targeting agents.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2008.04a
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• pp.77-86
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• 2008

It's been known that overexpression of the oncoprotein Her2 (eu/ErbB2), transmembrane receptor protein, occurs in human breast cancer. Her2-positive breast cancer patients who have Her2 overexpression show less therapeutic efficacy with enhanced metathesis and increased resistance to chemotherapy. So far, a humanized monoclonal antibody against Her2 protein called Herceptin is the only drug approved by Food and Drug Administration for treatment of Her2-overexpressing breast tumors. However, antibody therapy of Herceptin may not be ideal method for therapeutic intervention of Her2 protein expression. The therapeutic intervention of Her2 protein expression may be more efficiently achieved by inhibiting the expression of Her2 gene rather than by down-regulating the Her2 protein already overexpressed. Here, we found that the interaction of two proteins of ESX (an epithelial-restricted transcription factor) and DRIP130/CRSP130/Sur2 (a Ras-linked subunit of human mediator complexes) mediates the expression of Her2 gene. The association of ESX with Sur2 is mediated by a small hydrophobic face of 8-amino acid helix in ESX, suggesting that the ESX-Sur2 interaction can be a new novel target for Her2-positive cancer. The process to develop potent ESX-Sur2 interaction inhibitors targeting for Her2-positive cancer therapeutics will be discussed.