Heregulin-ß1-induced GPR30 upregulation promotes the migration and invasion potential of SkBr3 breast cancer cells via ErbB2/ErbB3-MAPK/ERK pathway.

Estrogen receptor (ER)-negative breast cancer cells are probably more aggressive with larger metastatic potential than ER-positive cells. Loss of ER in recurrent breast cancer is associated with poor response to endocrine therapy. G protein-coupled receptor 30 (GPR30) is expressed in half of ER-negative breast cancers. Tumor cell-derived heregulin-ß1 (HRG-ß1) is also found mainly in ER-negative cancer. In SkBr3 breast cancer cells that lack ER but express GPR30, HRG-ß1 upregulates mRNA and protein levels of GPR30 by promoting ErbB2-ErbB3 heterodimerization and activating the downstream MAPK-ERK signaling pathway. Moreover, GPR30 boosts HRG-ß1-induced migration and invasion of SkBr3 cells after combinative treatment with E2, 4-hydroxy-tamoxifen or the specific GPR30 agonist G-1, which are blocked by the specific GPR30 antagonist G-15 or the transfection with the small interfering RNA for GPR30. The ErbB2 inhibitor AG825 and the MEK1/2 inhibitor U0126 also partly inhibit the enhanced migration and invasion. Therefore, HRG-ß1-induced migration and invasion partly depend on the upregulation of GPR30 expression through activation of the ErbB2-ERK pathway in SkBr3 cells. The results of this study indicate that the crosstalk between GPR30 and HRGs signaling is important for endocrine therapy resistance and may provide a new therapeutic way to treat breast cancer.

Pathological significance of epidermal growth factor receptor expression and amplification in human gliomas.

AIMS: To investigate epidermal growth factor receptor (EGFR) expression and amplification in gliomas and to assess their association with survival. METHODS AND RESULTS: Immunohistochemistry and fluorescence in-situ hybridization were performed to analyse EGFR status in 158 cases of primary glioma. Kaplan-Meier survival and Cox regression analyses were performed to analyse the prognosis of patients. Overexpression of EGFR and expression of EGFR variant III (EGFRvIII) were found in 102 cases (64.6%) and 47 cases (29.7%), respectively. Overexpression of EGFR was significantly correlated with World Health Organization (WHO) grade and Karnofsky performance score (KPS) (both P < 0.05). Expression of EGFRvIII was significantly correlated with WHO grade, gender, age, and KPS (all P < 0.05). EGFR amplification was found in 46 cases (29.1%), and was significantly correlated with WHO grade, age, KPS and EGFR overexpression (all P < 0.05). Cox multifactor analysis showed that EGFR amplification was an independent unfavourable prognostic factor for human gliomas at all ages, and EGFRvIII was an independent prognostic factor in patients older than 60 years. CONCLUSION: EGFR amplification and EGFRvIII expression were associated with an unfavourable prognosis for patients of all ages, and for those older than 60 years, respectively. The differing significance of EGFR status in young and old glioma patients and its impact on prognosis needs further study.

Correlation of epidermal growth factor receptor overexpression with increased epidermal growth factor receptor gene copy number in esophageal squamous cell carcinomas.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignancies in China and epidermal growth factor receptor (EGFR) is widely distributed in human epithelial cell membrane. The aim of this study was to investigate the protein overexpression and gene copy number of EGFR in ESCC, and help to identify patients who may benefit from EGFR targeted therapies. METHODS: Immunohistochemistry (IHC) was performed to analyze the expression of EGFR in 105 cases of ESCC, 16 cases of squamous epithelial atypical hyperplasia, and 11 cases of normal esophageal tissue. Fluorescence in situ hybridization (FISH) was performed to analyze the gene copy number in 80 cases of ESCC, eight cases of squamous epithelial atypical hyperplasia, and eight samples of normal esophageal tissue. RESULTS: The IHC-positive rates of EGFR in 105 cases of ESCC, 16 cases of squamous epithelial atypical hyperplasia, and 11 normal esophageal tissues were 97% (102/105), 44% (7/16), and 18% (2/11) respectively. The difference in the expression of EGFR among different esophageal tissue groups had statistically significance (P < 0.05). Among the 105 cases of ESCC, overexpression of EGFR was found in 90 cases (86%), of which 55 cases scored 3+ for EGFR staining and 35 cases scored 2+. In ESCC, the expression of EGFR was significantly correlated with depth of invasion and TNM stage (P < 0.05), but not with other parameters. The FISH-positive rates of EGFR in 80 cases of ESCC, the eight cases of squamous epithelial atypical hyperplasia, and eight samples of normal esophageal tissue were 31.3% (25/80), 0 (0/8) and 0 (0/8) respectively. In ESCC, EGFR gene amplification was found in 17 (21%) cases, high polysomy in 8 (10%) cases, disomy in 34 cases, low trisomy in 17 cases, and high trisomy in four cases. EGFR FISH-positive was significantly correlated with depth of invasion and lymph node metastasis (P < 0.05). EGFR FISH-positive was significantly associated with overexpression of EGFR. CONCLUSION: Protein overexpression and/or increased gene copy number of EGFR is common in ESCC, and EGFR targeted therapy may be appropriate for ESCC patients.