A novel variant of human Grb7 is associated with invasive esophageal carcinoma.

Abstract

The cDNAs of a putative growth factor-bound (Grb) 7 signal transduction molecule and Grb7V novel splice variant were isolated from an invasive human esophageal carcinoma. Although both Grb7 isoforms share homology with the Mig-10 cell migration gene, the Grb7V isoform lacks 88 base pairs in the C terminus; the resultant frame shift leads to substitution of an SH2 domain with a short hydrophobic sequence. The wild-type Grb7 protein, but not the Grb7V isoform, is rapidly tyrosyl phosphorylated in response to EGF stimulation in esophageal carcinoma cells. Analysis of human esophageal tumor tissues and regional lymph nodes with metastases revealed that Grb7V was expressed in 40% of Grb7-positive esophageal carcinomas. More importantly, Grb7V expression was enhanced after metastatic spread to lymph nodes as compared to the original tumor tissues.

Coamplification and coexpression of GRB7 and ERBB2 is found in high grade intraepithelial neoplasia and in invasive Barrett's carcinoma

“…17 Conversely, expression of an antisense GRB7 RNA lowers endogenous grb7 protein levels and suppresses the in vitro invasive phenotype of these cells. 18 It is noteworthy to stress that we found GRB7 and ERBB2 coamplified and coexpressed in invasive adenocarcinoma and high grade intraepithelial neoplasia in Barrett's esophagus. Interestingly, other types of cancer show gene amplification without overexpression (e.g., gastric cancer 12 ) or mRNA overexpression without gene amplification (e.g., esophageal squamous cell carcinoma 18 ).…”

“…18 It is noteworthy to stress that we found GRB7 and ERBB2 coamplified and coexpressed in invasive adenocarcinoma and high grade intraepithelial neoplasia in Barrett's esophagus. Interestingly, other types of cancer show gene amplification without overexpression (e.g., gastric cancer 12 ) or mRNA overexpression without gene amplification (e.g., esophageal squamous cell carcinoma 18 ). Although an increase of DNA copy numbers and mRNA expression are well correlated, other mechanisms than gene amplification may induce mRNA overexpression such as gene mutation, modifications resulting in a prolonged half live of mRNA level or moderately increase elevated expression caused by polysomy of chromosome 17 as reported previously.…”

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

“…The importance of Grb7 in tumour progression has been suggested by several studies (Tanaka et al, 1997(Tanaka et al, , 1998(Tanaka et al, , 2000Han and Guan, 1999). Downregulating Grb7 either by anti-sense or siRNA technology has shown to inhibit the invasive (Tanaka et al, Figure 3 Effects of combined treatment with G7-18NATE-P and Doxorubicin on SK-BR-3 breast cancer cells.…”

Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2

“…Grb7 is not a substrate of the insulin receptor tyrosine kinase activity. In contrast, it has been reported that Grb7 is phosphorylated on tyrosine residues when it binds the EGF receptor and erbB2 (Pandey et al, 1996;Stein et al, 1994;Tanaka et al, 1998), but not the PDGF receptor (Yokote et al, 1996). Grb10 and Grb14, members of the same family of adapters, display similar properties: they bind various activated tyrosine kinase receptors, and if they are tyrosine phosphorylated by some of them (Mano et al, 1998) In vitro interaction between Grb7 domains and the insulin receptor.…”

“…The ®rst observation was the overexpression of Grb7 together with erbB2 in numerous breast tumors and cell lines (Stein et al, 1994). A variant of Grb7, lacking the C-terminus SH2 domain, is likely to be involved in the cell invasion and metastatic progression of human oesophageal carcinomas (Tanaka et al, 1998). Grb10 and Grb14 are also overexpressed in several breast and prostate cancer cell lines (Daly et al, 1996;Dong et al, 1997).…”