OBJECTIVETo evaluate the expression of the type I growth factor receptor family [epidermal growth factor receptor (EGFR), ErbB2 and ErbB3] by the epithelial cells in pterygium.

METHODSImmunoflourescent staining and Western blotting were performed to detect the expression pattern and quantity of EGFR, ErbB2 and ErbB3 proteins in the epithelia of 15 patients with primary pterygium and 12 subjects with normal conjunctiva.

RESULTSIn immunofluorescent staining, the EGFR protein was present in the basal cells while the ErbB2 and ErbB3 were expressed by the superficial cells in normal conjunctival epithelium. Of the pterygium cases 15, 11 were stained by EGFR, ErbB2 and ErbB3 in the full thickness of the epithelium and showed stronger staining compared with the control group. Four of them showed a similar staining pattern to the normal conjunctiva group. The density of protein bands detected by Western blotting for all three growth factor receptors was consistent with the immunofluorescent staining. Compared with normal conjunctiva, stronger protein bands of these three receptors were found in all of the pterygium specimens, in which EGFR, ErbB2 and ErbB3 were expressed in the full thickness, as shown by immunofluorescent staining.

CONCLUSIONSThe increased expression of EGFR, ErbB2 and ErbB3 proteins was present in pterygium, which indicated that pterygium is a disorder with abnormal proliferation. The abnormal expression of EGFR, ErbB2 and ErbB3 by the epithelium and the communication with cytokines in the stroma in pterygium may be a key pathogenic factor in this disorder.

Adult ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Pterygium ; metabolism ; Receptor, Epidermal Growth Factor ; metabolism ; Receptor, ErbB-2 ; metabolism ; Receptor, ErbB-3 ; metabolism

OBJECTIVETo study the association of human epidermal growth factor receptor family molecules expression in gastric cancer tissues with the prognosis of patients with gastric cancer.

METHODSClinical data of 161 patients with gastric cancer undergoing gastrectomy in Jiangsu Cancer Hospital between January 2006 and January 2007 were analyzed retrospectively. The expression of HER1, HER2, HER3 and HER4 was detected by immunohistochemistry. Association of the expression of HER family with the prognosis of patients was examined. Kaplan-Meier method was used to analyze the survival.

RESULTSHigh expression rates of HER1, HER2, HER3 and HER4 were 46.0% (74/161), 10.6% (17/161),55.9% (90/161) and 68.3% (110/161) respectively. Univariate analysis revealed that high expression of HER3 was associated with tumor invasion depth, lymph node metastasis, stage, neurovascular invasion, and overall 4-year survival. High expression of HER4 was associated with tumor distant metastasis and stage. High co-expression of HER2 and HER3 was associated with overall 4-year survival (P=0.023). Multivariate analysis revealed that high expression of HER3 and stage were prognostic independent factors.

CONCLUSIONUp-regulated expression of HER3 is associated with the poor prognosis in gastric cancer patients.

Adult ; Aged ; Aged, 80 and over ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Middle Aged ; Prognosis ; Receptor, Epidermal Growth Factor ; metabolism ; Receptor, ErbB-2 ; metabolism ; Receptor, ErbB-3 ; metabolism ; Receptor, ErbB-4 ; Retrospective Studies ; Stomach Neoplasms ; metabolism ; pathology

Adult ; Aged ; Carcinoma, Hepatocellular ; metabolism ; Female ; Humans ; Liver Neoplasms ; metabolism ; Male ; Middle Aged ; RNA, Messenger ; biosynthesis ; genetics ; Receptor, ErbB-2 ; biosynthesis ; genetics ; Receptor, ErbB-3 ; biosynthesis ; genetics

OBJECTIVE: To explore expression of ErbB3 and ErbB4 genes in laryngeal squamous cell carcinomas and their relation with the biological and clinicopathological parameters. METHOD: Expression of ErbB3 and ErbB4 mRNA in 36 cases of laryngeal carcinomas and normal mucosa of incisal margin, 11 cases of benign proliferative lesions were examined by reverse transcription polymerase chain reaction (RT-PCR). RESULT: In laryngeal carcinomas and benign proliferative lesions, over-expressive positive ratios of ErbB3 were 66.7%, 18.2% respectively (P < 0.01). However, that of ErbB4 were 25.0%, 9.1% respectively (P > 0.05). Differences of expressive level of ErbB3 and ErbB4 were not significant between laryngeal carcinoma and normal mucous of incisal margin (P > 0.05). In addition, expressive level of ErbB3 and ErbB4 were not associated with diversity of clinical pathologic characters (P > 0.05). CONCLUSION ErbB3 and ErbB4 genes play different role in carcinogenesis and development, and relate to the reoccurrence of carcinoma.
Adult ; Aged ; Carcinoma, Squamous Cell ; metabolism ; pathology ; ErbB Receptors ; genetics ; metabolism ; Female ; Humans ; Laryngeal Neoplasms ; metabolism ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; RNA, Messenger ; genetics ; Receptor, ErbB-3 ; genetics ; metabolism ; Receptor, ErbB-4

OBJECTIVETo study the growth regulation pathway and the mechanism of acquired resistance to tamoxifen (TAM) in breast cancer cells.

METHODSTAM was used to induce wild-type MCF-7 human breast cancer cell line and establish a tamoxifen-resistant (TAM-R) cell line. RT-PCR, Western blot and immuocytochemical techniques were used to detect and compare mRNA and protein of c-erbB1, cerbB2, c-erbB3, c-erbB4 in wild-type MCF-7 and TAM-R MCF-7 cell lines.

RESULTSCompared with wild-type MCF-7 cells, the mRNA of c-erbB1 increased 6 times (P < 0.05) and the protein 3 times higher (P < 0.05), and the mRNA of c-erbB2 increased 3 times (P < 0.05) and the protein 1.5 times higher (P < 0.05) in TAM-R MCF-7 cells. However, comparable levels of c-erbB3 mRNA and protein were expressed in both cell lines. c-erbB4 could not be detected. Under basic conditions, phosphorylated c-erbB1/c-erbB2 and c-erbB1/c-erbB3 heterodimers but not c-erbB2/c-erbB3 receptor heterodimers were detected in TAM-R cells in association with increased level of phosphorylated MAPK.

CONCLUSIONOur findings demonstrated that the development of TAM-resistance in MCF-7 cells is related with the autocrine release and action of an c-erbB1-specific ligand inducing preferential c-erbB1/c-erbB2 dimerization and downstream activation of the MAPK pathway.

Antineoplastic Agents, Hormonal ; pharmacology ; Blotting, Western ; Breast Neoplasms ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Female ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Immunohistochemistry ; Mitogen-Activated Protein Kinases ; metabolism ; Phosphorylation ; drug effects ; RNA, Messenger ; biosynthesis ; genetics ; Receptor, Epidermal Growth Factor ; biosynthesis ; genetics ; Receptor, ErbB-2 ; biosynthesis ; genetics ; Receptor, ErbB-3 ; biosynthesis ; genetics ; Receptor, ErbB-4 ; Reverse Transcriptase Polymerase Chain Reaction ; Tamoxifen ; pharmacology

Amino Acid Substitution ; Antineoplastic Agents/pharmacology* ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; Gastrointestinal Neoplasms/pathology* ; Humans ; MAP Kinase Signaling System/genetics* ; Mutation, Missense ; Receptor, ErbB-3/metabolism* ; Receptor, Fibroblast Growth Factor, Type 1/metabolism*

In the present study, we investigate the expression profile of the epidermal growth factor receptor family, which comprises EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4 in oral leukoplakia (LP). The expression of four epidermal growth factor receptor (EGFR) family genes and their ligands were measured in LP tissues from 14 patients and compared with levels in 10 patients with oral lichen planus (OLP) and normal oral mucosa (NOM) from 14 healthy donors by real-time polymerase chain reaction (PCR) and immunohistochemistry. Synchronous mRNA coexpression of ErbB1, ErbB2, ErbB3 and ErbB4 was detected in LP lesions. Out of the receptors, only ErbB4 mRNA and protein was more highly expressed in LP compared with NOM tissues. These were strongly expressed by epithelial keratinocytes in LP lesions, as shown by immunohistochemistry. Regarding the ligands, the mRNA of Neuregulin2 and 4 were more highly expressed in OLP compared with NOM tissues. Therefore, enhanced ErbB4 on the keratinocytes and synchronous modulation of EGFR family genes may contribute to the pathogenesis and carcinogenesis of LP.
Adult ; Aged ; Amphiregulin ; Betacellulin ; EGF Family of Proteins ; Epidermal Growth Factor ; metabolism ; Epiregulin ; Female ; Gene Expression Profiling ; Glycoproteins ; metabolism ; Heparin ; metabolism ; Heparin-binding EGF-like Growth Factor ; Humans ; Intercellular Signaling Peptides and Proteins ; metabolism ; Keratinocytes ; metabolism ; Leukoplakia, Oral ; metabolism ; Lichen Planus, Oral ; metabolism ; Ligands ; Male ; Middle Aged ; Mouth Mucosa ; metabolism ; Nerve Growth Factors ; Neuregulins ; metabolism ; RNA, Messenger ; metabolism ; Real-Time Polymerase Chain Reaction ; Receptor, Epidermal Growth Factor ; metabolism ; Receptor, ErbB-2 ; metabolism ; Receptor, ErbB-3 ; metabolism ; Receptor, ErbB-4 ; Receptors, Cell Surface ; metabolism ; Transforming Growth Factor alpha ; metabolism ; Up-Regulation ; physiology

Overexpression of HER2 correlates with more aggressive tumors and increased resistance to cancer chemotherapy. However, a functional comparison between the HER2high/HER3 and the HER2low/HER3 dimers on tumor metastasis has not been conducted. Herein we examined the regulation mechanism of heregulin-beta1 (HRG)-induced MMP-1 and -9 expression in breast cancer cell lines. Our results showed that the basal levels of MMP-1 and -9 mRNA and protein expression were increased by HRG treatment. In addition, HRG-induced MMP-1 and -9 expression was significantly decreased by MEK1/2 inhibitor, U0126 but not by phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294002. To confirm the role of MEK/ERK pathway on HRG-induced MMP-1 and -9 expression, MCF7 cells were transfected with constitutively active adenoviral-MEK (CA-MEK). The level of MMP-1 and -9 expressions was increased by CA-MEK. MMP-1 and -9 mRNA and protein expressions in response to HRG were higher in HER2 overexpressed cells than in vector alone. The phosphorylation of HER2, HER3, ERK, Akt, and JNK were also significantly increased in HER2 overexpressed MCF7 cells compared with vector alone. HRG-induced MMP-1 and -9 expressions were significantly decreased by lapatinib, which inhibits HER1 and HER2 activity, in both vector alone and HER2 overexpressed MCF7 cells. Finally, HRG-induced MMP-1 and MMP-9 expression was decreased by HER3 siRNA overexpression. Taken together, we suggested that HRG-induced MMP-1 and MMP-9 expression is mediated through HER3 dependent pathway and highly expressed HER2 may be associated with more aggressive metastasis than the low expressed HER2 in breast cancer cells.
Breast Neoplasms/enzymology/*genetics/*metabolism ; Butadienes/pharmacology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Female ; Gene Expression ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; MAP Kinase Signaling System ; MCF-7 Cells ; Matrix Metalloproteinase 1/*genetics/metabolism ; Matrix Metalloproteinase 9/*genetics/metabolism ; Neuregulin-1/*pharmacology ; Nitriles/pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Multimerization ; Proto-Oncogene Proteins c-akt/metabolism ; Quinazolines/pharmacology ; Receptor, erbB-2/genetics/*metabolism ; Receptor, erbB-3/*metabolism

Dimerization among the EGFR family of tyrosine kinase receptors leads to allosteric activation of the kinase domains of the partners. Unlike other members in the family, the kinase domain of HER3 lacks key amino acid residues for catalytic activity. As a result, HER3 is suggested to serve as an allosteric activator of other EGFR family members which include EGFR, HER2 and HER4. To study the role of intracellular domains in HER3 dimerization and activation of downstream signaling pathways, we constructed HER3/HER2 chimeric receptors by replacing the HER3 kinase domain (HER3-2-3) or both the kinase domain and the C-terminal tail (HER3-2-2) with the HER2 counterparts and expressed the chimeric receptors in Chinese hamster ovary (CHO) cells. While over expression of the intact human HER3 transformed CHO cells with oncogenic properties such as AKT/ERK activation and increased proliferation and migration, CHO cells expressing the HER3-2-3 chimeric receptor showed significantly reduced HER3/HER2 dimerization and decreased phosphorylation of both AKT and ERK1/2 in the presence of neuregulin-1 (NRG-1). In contrast, CHO cells expressing the HER3-2-2 chimeric receptor resulted in a total loss of downstream AKT activation in response to NRG-1, but maintained partial activation of ERK1/2. The results demonstrate that the intracellular domains play a crucial role in HER3's function as an allosteric activator and its role in downstream signaling.
Amino Acid Sequence ; Animals ; CHO Cells ; Cell Movement ; Cell Proliferation ; Cricetinae ; Cricetulus ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Humans ; Intracellular Space ; enzymology ; MAP Kinase Signaling System ; Models, Molecular ; Molecular Sequence Data ; Phosphatidylinositol 3-Kinases ; metabolism ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-akt ; metabolism ; Receptor, ErbB-2 ; chemistry ; Receptor, ErbB-3 ; chemistry ; genetics ; metabolism ; Recombinant Fusion Proteins ; chemistry ; genetics ; metabolism ; Signal Transduction

BACKGROUND AND OBJECTIVEThe effect of gefitinib on advanced non-small cell lung cancer (NSCLC) was various. How to choose the sensitive patients and improve the effect was difficulty in clinic. This study was to assess the correlation of epidermal growth factor receptor (EGFR) mutations and HER2/3 protein expression with the effect of gefitinib on Chinese patients with advanced NSCLC.

METHODSFrom May 2002 to February 2005, a total of 106 Chinese NSCLC patients who had failed at least one chemotherapy regimen were treated with gefitinib 250 mg once a day. The mutations in the exons 18-24 of EGFR gene were detected in the tumor tissues from 106 patients before the treatment of gefitinib, and HER2/3 expression in 84 tumor samples were detected by immunohistochemistry.

RESULTSMutation was identified in 32 (30.2%) tumor tissues. Overall remission rate was significantly higher in the HER2 high expression patients than in the HER2 low expression patients (36.8% vs 17.4%, P=0.044). HER2 and HER3 expression levels were not associated with time to progression (TTP) and overall survival (OS). The patients with HER2/3 single high expression had relatively longer TTP and OS than those with HER2/3 single low expression (6.1 vs 9.1 months, P=0.725; 6.1 vs 9.0 months, P=0.862), while those with concomitant HER2/3 high expression had significant longer TTP and OS. EGFR-mutated patients with HER2 expression or high HER2 and HER3 expressions were more sensitive to gefitinib.

CONCLUSIONEGFR mutations combined with HER2/3 expressions is a significant predictor for gefitinib efficacy on Chinese patients with advanced NSCLC.

Adenocarcinoma ; drug therapy ; genetics ; metabolism ; pathology ; Adult ; Aged ; Antineoplastic Agents ; therapeutic use ; Asian Continental Ancestry Group ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; metabolism ; Carcinoma, Squamous Cell ; drug therapy ; genetics ; metabolism ; pathology ; Exons ; Female ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Mutation ; Neoplasm Staging ; Quinazolines ; therapeutic use ; Receptor, Epidermal Growth Factor ; genetics ; Receptor, ErbB-2 ; metabolism ; Receptor, ErbB-3 ; metabolism ; Remission Induction ; Survival Rate