• Title, Summary, Keyword: ErbB

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Expression of Heregulin and ErbB Family Proteins in Gastric Adenocarcinomas: Correlation with Clinopathologic Prognostic Factors (위선암에서 Heregulin과 ErbB Family 단백 발현과 임상.병리학적 예후인자와의 상관관계)

  • Yoo, Chang-Hak;Lee, Ju-Han;Choi, Jong-Sang
    • Journal of Gastric Cancer
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    • v.6 no.3
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    • pp.181-188
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    • 2006
  • Purpose: Heregulin is a natural ligand for erbB3 and erbB4. However, very little is known about their roles in the gastric cancer This retrospective study was performed to evaluate the frequencies of heregulin and erbB family protein expression and to compare their expressions with clinicopathologic parameters. Materials and Methods: Immunohistochemical expressions of heregulin and erbB family proteins were examined with tissue micro-array slides. A total of 251 gastric adenocarcinomas were classified as early cancers and advanced cancers and as having and not having lymph node metastases. Results: The positive rates of the heregulin, erbB1, erbB2, erbB3, and erbB4 protein stainings were 64%, 68%, 6%, 88%, and 76%, respectively. Intestinal type gastric adenocarcinomas showed higher expression of heregulin, erbB2, erbB3, and erbB4 proteins. Heregulin and erbB4 proteins showed lower expressions in advanced gastric carcinomas. However, erbB2 protein showed higher expression in advanced gastric carcinomas. The protein expressions of heregulin and erbB family proteins showed no relationship with survival rate. Co-expression groups of heregulin and erbB3 proteins or heregulin and erbB4 proteins showed higher expressions in intestinal type adenocarcinomas and early gastric carcinomas. Conclusion: Heregulin, erbB3, and erbB4 proteins may play a role in the early stage of adenocarcinomas.

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ErbB2 kinase domain is required for ErbB2 association with β-catenin (ErbB2의 kinase 영역이 β-catenin과 ErbB2의 결합에 필요하다)

  • Ha, Nam-Chul;Xu, Wanping;Neckers, Len;Jung, Yun-Jin
    • Journal of Life Science
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    • v.17 no.3
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    • pp.356-361
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    • 2007
  • To investigate the region of ErbB2 for the $ErbB2-{\beta}-catenin$ interaction, a proteasome $resistant-{\beta}-catenin$ and various ErbB2 constructs were transfected in COS7 cells. ErbB2 proteins were immunoprecipitated, and coimmunoprecipitated ${\beta}-catenin$ was examined by Western blotting. ${\beta}-catenin$ coimmunoprecipitated with full length ErbB2. Of the truncated ErbB2 proteins DT (1-1123), DHC (1-1031) and DK (1-750), the ErbB2 constructs containing the kinase domain, DT and DHC, precipitated together with ${\beta}-catenin$ but DK containing no kinase domain did not. To further test the requirement of the kinase domain for ${\beta}-catenin-ErbB2$ interaction, the presence of ${\beta}-catenin$ in the immunocomplex was examined following transfection with an ErbB2 mutant (${\triangle}750-971$) whose kinase domain is internally deleted and subsequent immunoprecipitation of the ErbB2 mutant. ${\beta}-catenin$ was not detected in the immunocomplex. These results suggest that the ErbB2 kinase domain comprises a potential site for ${\beta}-catenin$ binding to the receptor tyrosine kinase.

The use of culture systems for the study of oligodendrocyte development and injury: The erbB2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes

  • Park, Song-Kyu;Kim, Hwan-Mook;Vartanian, Timothy
    • Proceedings of the Korea Environmental Mutagen Society Conference
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    • pp.14-23
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    • 2002
  • Development of oligodendrocytes and the generation of myelin internodes within the spinal cord depends on regional signals derived from the notochord and axonally derived signals. Neuregulin (NRG)-1, localized in the floor plate as well as in motor and sensory neurons, is necessary for normal oligodendrocyte development. Oligodendrocytes respond to NRGs by activating members of the erbB receptor tyrosine kinase family. Here, we show that erbB2 is not necessary for the early stages of oligodendrocyte precursor development, but is essential for proligodendroblasts to differentiate into galactosylcerebroside-positive (GalC+) oligodendrocytes. In the presence of erbB2, oligodendrocyte development is normal. In the absence of erbB2 (erbB2-/-), however, oligodendrocyte development is halted at the proligodendroblast stage with a >10-fold reduction in the number of GalC+ oligodendrocytes. ErbB2 appears to function in the transition of proligodendroblast to oligodendrocyte by transducing a terminal differentiation signal, since there is no evidence of increased oligodendrocyte death in the absence of erbB2. Furthermore, known survival signals for oligodendrocytes increase oligodendrocyte numbers in the presence of erbB2, but fail to do so in the absence of erbB2. Of the erbB2-/- oligodendrocytes that do differentiate, all fail to ensheath neurites. These data suggest that erbB2 is required for the terminal differentiation of oligodendrocytes and for development of myelin.

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Role of Shc and Phosphoinositide 3-Kinase in Heregulin-Induced Mitogenic Signaling via ErbB3

  • Kim, Myong-Soo;Koland, John G.
    • 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.

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Immunohistochemical Study of C-erbB-2 and VEGF Expression in Non-Small Cell Lung Cancer (비소세포 폐암에서 C-erbB-2와 VEGF 발현에 대한 면역조직화학적 연구)

  • Shin, Jong Wook;Ha, Kyung Won;Choi, Jae Cheol;Kim, Jae Yeol;Park, In Whon;Choi, Byoung Whui;Yoo, Jae Hyung
    • Tuberculosis and Respiratory Diseases
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    • v.62 no.1
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    • pp.43-50
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    • 2007
  • Background: Mutated or deregulated expression of C-erbB-2 causes this gene to function as a potent oncogene. Vascular endothelial growth factor (VEGF) is a crucial angiogenic molecule in lung cancer. Both C-erbB-2 and VEGF can promote growth, proliferation and metastasis in non-small cell lung cancer (NSCLC). The purpose of this study was to investigate evaluate the relationship between the expressions of the C-erbB-2 and VEGF genes using immunohistochemistry. Materials and Methods: Ninety-five patients with NSCLC were involved (60 squamous cell carcinoma and 35 adenocarcinoma). The formalin-fixed paraffin embedded specimens were immunohistochemically stained for C-erbB-2 and VEGF using the avidin-biotin complex method. Results: Positive C-erbB-2 expression was observed more often in adenocarcinomas than squamous cell carcinomas (p<0.05). Although the immunohistochemical expressions of C-erbB-2 and VEGF in non-small-cell lung cancer showed increased tendencies at an advanced stage, the correlation between early and advanced cancers was insignificant. In adenocarcinomas, the expressions of VEGF and C-erbB-2 were significantly (p<0.05). Conclusion: The overexpression fo C-erbB-2 was significantly higher in adenocarcinomas than squamous cell carcinomas, and correlated with the expression of VEGF in adenocarcinomas of the lungs.

Effect of Carotenoids on the Growth of HT-29 Human Colon Cancer Cells (Carotenoids가 인체의 대장암 세포인 HT-29 세포의 증식에 미치는 영향)

  • ;;;;Frederick Khachik
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.32 no.3
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    • pp.428-436
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    • 2003
  • Epidemiological studies have observed a negative association between increased consumption of green and yellow vegetables and cancer incidence. These vegetables contain carotenoids, which are reported to exhibit anticarcinogenic effects. Overexpression of ErbB2 and ErbB3 genes is a frequent event in several human cancers. The present study was performed to determine whether $\alpha$-carotene, $\beta$-carotene, lutein, or lycopene inhibits cell growth and to assess such an effect is related to changes in the levels of the ErbB receptor family and tile ErbB3 receptor signaling pathway in HT-29 cells. HT-29 cells were cultured in serum-free medium in the presence of various concentrations (0~100 $\mu$M) of the individual carotenoids. $\alpha$ -Carotene and lycopene significantly inhibited cell growth in a dose-dependent manner, whereas lutein slightly inhibited cell growth and $\beta$-carotene increased cell growth. Lycopene is more potent than $\alpha$ -carotene in inhibiting HT-29 cell growth. Lycopene inhibited DNA synthesis and induced apoptosis of HT-29 cells. The ErbB3 ligand heregulin (HRG) increased cell growth but did not prevent the lycopene-induced inhibition of cell growth. Lycopene decreased ErbB2 protein levels in a dose-dependent manner. Immunoprecipitation/Western blot studies revealed that lycopene inhibited HRG-induced phosphorylation of ErbB3, recruitment of the 985 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) to the ErbB3 receptor, and phosphorylation of Akt. These results indicate that downregulation of ErbB2/ErbB3/PI3K/Akt signaling may be one of the mechanisms by which lycopene inhibits HT-29 cell pro-liferation and induces apoptosis.

Expression of ErbB receptors in the pre-pubertal and pubertal virgin mammary glands of dairy cows

  • Lee, Byung-Woo;Kim, Yo-Han;Jeon, Byung-Suk;Singh, Naresh Kumar;Kim, Won-Ho;Kim, Meing-Jooung;Yoon, Byung-Il
    • Korean Journal of Veterinary Research
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    • v.52 no.4
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    • pp.269-273
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    • 2012
  • In the present study, we investigated the expression patterns of ErbB family proteins in the pre-pubertal and pubertal mammary glands of dairy cows in association with gland development. For this study, we performed immunohistochemistry for ErbB-1-4 and Ki-67 cell proliferation marker. We found that the pre-pubertal and pubertal mammary glands had typical structures, including ducts and terminal end buds embedded in the stroma, and no development of lobuloalveolar structures. On immunohistochemistry, ErbB-2 and ErbB-3 were strongly expressed in the cytoplasm and nuclei in the epithelial cells of mammary ducts and terminal end buds, and stromal cells, whereas ErbB-1 and ErbB-4 were weakly expressed only in the cytoplasm of gland epithelium and stromal cells, irrespective of the developmental stage. Cell proliferation was inactive in the mammary gland cell compartments in both phases. Thus, expression of the ErbB family in the developing mammary glands was not associated with their functional effects, such as cell proliferation and lobuloalveolar development. In conclusion, ErbB receptors were differentially expressed in the epithelial and stromal cells of virgin mammary glands of dairy cows. Compared with rodent mammary glands, ErbB-3 and ErbB-4 were found to be highly expressed in bovine mammary glands.

Relationship between erb-B2 mRNA Expression in Blood and Tissue of Invasive Ductal Carcinoma Breast Cancer Patients and Clinicopathological Characteristics of the Tumors

  • Moazzezy, Neda;Ebrahimi, Fatemeh;Sisakht, Mahsa Mollapour;Yahyazadeh, Hossein;Bouzari, Saeid;Oloomi, Mana
    • 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.

Effect of Epigallocatechin Gallate on Inhibition of Cell Proliferation in MDA-MB-231 Human Breast Cancer Cells (Epigallocatechin Gallate가 인체 유방암 세포인 MDA-MB-231의 세포증식억제에 미치는 영향)

  • Hong, Eun-Jung;Kim, Woo-Kyung
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.36 no.8
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    • pp.983-988
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    • 2007
  • Epigallocatechin gallate (EGCG), a principal antioxidant derived from green tea, is one of the most extensively investigated chemopreventive phytochemicals. However, the effect of EGCG on proliferation in MDA-MB-231 breast cancer cell is not well known. We investigated the effect of EGCG on protein and mRNA expression related to cell proliferation in MDA-MB-231 human breast cancer cell lines. We cultured MDA-MB-231 cells in the presence of 0, 5, 10 and 20 ${\mu}m$ of EGCG. EGCG significantly inhibited the cancer cell proliferation (p<0.05). In MDA-MB-231 huamn breast cancer cell, EGCG lowered $ErbB_2$ and $ErbB_3$ protein as well as mRNA expression. In addition, protein and mRNA expression of phosphorylated Akt and total Akt were significantly decreased (p<0.05). We suggest that EGCG inhibits cell proliferation through $ErbB_2$, $ErbB_3$ and Akt cell signaling.

Macrophage inhibitory cytokine-1 transactivates ErbB family receptors via the activation of Src in SK-BR-3 human breast cancer cells

  • Park, Yun-Jung;Lee, Han-Soo;Lee, Jeong-Hyung
    • BMB Reports
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    • v.43 no.2
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    • pp.91-96
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    • 2010
  • The function of macrophage inhibitory cytokine-1 (MIC-1) in cancer remains controversial, and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of EGFR, ErbB2, and ErbB3 through the activation of c-Src in SK-BR-3 breast cells. MIC-1 induced significant phosphorylation of EGFR at Tyr845, ErbB2 at Tyr877, and ErbB3 at Tyr1289 as well as Akt and p38, Erk1/2, and JNK mitogen-activated protein kinases (MAPKs). Treatment of SK-BR-3 cells with MIC-1 increased the phosphorylation level of Src at Tyr416, and induced invasiveness of those cells. Inhibition of c-Src activity resulted in the complete abolition of MIC-1-induced phosphorylation of the EGFR, ErbB2, and ErbB3, as well as invasiveness and matrix metalloproteinase (MMP)-9 expression in SK-BR-3 cells. Collectively, these results show that MIC-1 may participate in the malignant progression of certain cancer cells through the activation of c-Src, which in turn may transactivate ErbB-family receptors.