Study of c‐erbB‐2 protein and epidermal growth factor receptor expression and DNA ploidy pattern in colorectal carcinoma

Nakae, Shiro; Shimada, E; Urakawa, Tomoaki

doi:10.1002/jso.2930540412

Cited by 17 publications

(9 citation statements)

References 22 publications

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“…Besides gene amplification, several investigators have described the involvement of ETS family (Scott et al, 2000) and AP-2 family (Bates and Hurst, 1997) transcription factors in the gene overexpression. ERBB2 overexpression has also been reported in cancers of colon (Nakae et al, 1993;Kapitanovic et al, 1994;Maurer et al, 1998), prostate (Ross et al, 1993;Morote et al, 1999), ovary (Fajac et al, 1995) and pancreatic (Yamanaka et al, 1993) origin. However, the mechanisms leading to increased expression of the gene have not been investigated in these tumours.…”

Section: Discussionmentioning

confidence: 92%

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Vernimmen¹,

Guéders²,

Pisvin

et al. 2003

Br J Cancer

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The ERBB2 gene is overexpressed in 30% of breast cancers and this has been correlated with poor prognosis. ERBB2 is upregulated in other cancers such as prostate, pancreas, colon and ovary. In breast cancer cells, the mechanisms leading to ERBB2 gene overexpression are increased transcription and gene amplification. In these cancers, AP-2 transcription factors are involved in ERBB2 overexpression, and AP-2 levels are correlated with p185 c-erbB-2 levels. In this work, we wanted to know if the same molecular mechanisms are responsible for the ERBB2 upregulation in non-breast cancers. We compared ERBB2 gene copy number, p185 c-erbB-2 and mRNA levels with AP-2 levels in several ovary, prostate, colon and pancreas cancer cells. A moderate expression of erbB-2 mRNA and protein were observed in some cells without gene amplification. In contrast to breast cancer cells, AP-2 factors were absent or low in some non-breast cells which did express ERBB2. It is thus likely that AP-2 is not a major player in the increased levels of erbB-2 transcripts in non-breast cancer cells. The transcriptional activity of the ERBB2 promoter in colon and ovary cancer cells was estimated using reporter vectors. The results showed that the promoter regions involved in ERBB2 gene overexpression in breast cancer cells are different from those that lead to the gene upregulation in colon and ovary cancers. In conclusion, our results indicate that different transcriptional and post-transcriptional mechanisms are responsible for the increased levels of erbB-2 transcript and protein in breast and non-breast cancer cells.

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Section: Discussionmentioning

confidence: 92%

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Vernimmen¹,

Guéders²,

Pisvin

et al. 2003

Br J Cancer

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“…Previous IHC studies examining HER-2 expression reported different percentages of positive cells, ranging from 0 to 100%. [16][17][18][19][20][21][22][23][24] The major cause of these discrepancies seems to be the different criteria for evaluating the results. Studies that scored intracytoplasmic staining as positive reported larger frequencies, whereas studies that reported only membrane staining as positive was scored lower or zero frequency.…”

Section: Discussionmentioning

confidence: 99%

Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study

et al. 2004

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Overexpression of HER-2 and the epidermal growth factor receptor (EGFR) has been observed in many cancers, sometimes accompanied by gene amplification. To assess whether novel chemotherapies targeting these overexpressed proteins may be effective for the treatment of colorectal cancers, we examined the exact frequency of HER-2 and EGFR overexpression, the relationship between gene amplification and protein expression, and the heterogeneity of gene amplification within and between primary and metastatic tumors. We evaluated 244 colorectal cancers immunohistochemically. All tumors found to overexpress HER-2 or EGFR were further analyzed for gene amplification by fluorescent in situ DNA hybridization. Overexpression of HER-2 and EGFR was found in 8 (3%) and 19 (8%) of the 244 colorectal carcinomas, respectively. Gene amplification was observed in 100 and 58% of the tumors exhibiting HER-2 and EGFR overexpression, respectively. HER-2 amplification in cancer cells was characterized by clusters of hybridization signals, suggesting amplicons in homogeneously staining regions that were predominant in most primary and metastatic tumors. EGFR amplification, observed as scattered signals reminiscent of amplicons in double minute chromosomes, or coamplification of EGFR with the centromeric regions was observed as a minor population within primary tumors, and found in variety of populations in metastatic tumors. Overexpression of HER-2 and EGFR were observed in only a small fraction of colorectal carcinomas, but were frequently accompanied by gene amplification. The HER-2 gene is located on chromosomal region 17q11.2-q12 and the EGFR gene is located on 7p12. These encode 185 kDa (p185) and 170 kDa plasma membrane glycoproteins, respectively. They share approximately 50% overall homology and are composed of an N-terminus extracellular ligand-binding domain, a transmembrane lipophilic segment, and a C-terminus intracellular region containing a tyrosine kinase domain.

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“…Constitutive tyrosine activation of h-catenin (24,25) and several protein tyrosine kinases, such as c-Kit (26), c-erbB2 (27), c-Met (28), and pp60(c-Src) (29)(30)(31)(32), is frequently observed in premalignant colorectal lesions. It was also reported that an antisense-mediated down-regulation of pp60(c-Src) expression severely decreased tumorigenicity of HT29 colon adenocarcinoma cells (33), although potential transcriptional targets of pp60(c-Src) still remained elusive.…”

Section: Introductionmentioning

confidence: 99%

SKI-606 Decreases Growth and Motility of Colorectal Cancer Cells by Preventing pp60(c-Src)–Dependent Tyrosine Phosphorylation of β-Catenin and Its Nuclear Signaling

Benati²,

et al. 2006

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Inhibition of deregulated protein tyrosine kinases represents an attractive strategy for controlling cancer growth. However, target specificity is an essential aim of this strategy. In this report, pp60(c-Src) kinase and B-catenin were found physically associated and constitutively activated on tyrosine residues in human colorectal cancer cells. The use of specific smallinterfering RNAs (siRNA) validated pp60(c-Src) as the major kinase responsible for B-catenin tyrosine phosphorylation in colorectal cancer. Src-dependent activation of B-catenin was prevented by SKI-606, a novel Src family kinase inhibitor, which also abrogated B-catenin nuclear function by impairing its binding to the TCF4 transcription factor and its transactivating ability in colorectal cancer cells. These effects were seemingly specific, as cyclin D1, a crucial B-catenin/TCF4 target gene, was also down-regulated by SKI-606 in a dosedependent manner accounting, at least in part, for the reduced growth (IC 50 , 1.5-2.4 Mmol/L) and clonogenic potential of colorectal cancer cells. Protein levels of B-catenin remained substantially unchanged by SKI-606, which promoted instead a cytosolic/membranous retention of B-catenin as judged by immunoblotting analysis of cytosolic/nuclear extracts and cell immunofluorescence staining. The SKI-606-mediated relocalization of B-catenin increased its binding affinity to E-cadherin and adhesion of colorectal cancer cells, with ensuing reduced motility in a wound healing assay. Interestingly, the siRNA-driven knockdown of B-catenin removed the effect of SKI-606 on cell-to-cell adhesion, which was associated with prolonged stability of E-cadherin protein in a pulse-chase experiment. Thus, our results show that SKI-606 operates a switch between the transcriptional and adhesive function of B-catenin by inhibiting its pp60(c-Src)-dependent tyrosine phosphorylation; this could constitute a new therapeutic target in colorectal cancer. (Cancer Res 2006; 66(4): 2279-86)

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Study of c‐erbB‐2 protein and epidermal growth factor receptor expression and DNA ploidy pattern in colorectal carcinoma

Cited by 17 publications

References 22 publications

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study

SKI-606 Decreases Growth and Motility of Colorectal Cancer Cells by Preventing pp60(c-Src)–Dependent Tyrosine Phosphorylation of β-Catenin and Its Nuclear Signaling

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