c-erbB-2 (HER-2/neu) gene amplification is a better indicator of poor prognosis than protein over-expression in operable breast-cancer patients

Abstract

We investigated the effect of hepatocyte-derived extracellular matrix (ECM) on the expression of erb-B2 and erb-B3 in colon cancer cell lines, as well as the role of erb-B2 and erb-B3 in colon cancer cell proliferation. Colon cancer cell lines plated on hepatocyte-derived ECM had increased protein levels of both erb-B2 and erb-B3. The addition of soluble recombinant proteoglycan syndecan-4 also resulted in higher expression of erb-B2 and erb-B3. We prepared hepatocytederived ECM from 1 to 7 days' cultures of hepatocytes, which contained different amounts of sulfated glycosaminoglycans. There was a direct correlation between the amounts of sulfated glycosaminoglycans in the ECM and the levels of erb-B2 and erb-B3 in the colon cell line KM12. The stimulatory effect of hepatocyte-derived ECM was abolished when the colon cancer cells were cultured in the presence of antibodies to erb-B2. These studies show that hepatocyte-derived ECM and the heparan sulfate proteoglycans present in it are responsible for inducing erb-B2 and erb-B3 in colon cancer cells. The growth stimulatory effect of extracellular matrix is mediated, at least in part, by increased expression of erb-B2 and erb-B3. © 2001 Wiley-Liss, Inc. Key words: extracellular matrix; colon cancer; heparan sulfateThe local milieu of various organs colonized by metastatic tumor cells, in particular the extracellular matrix (ECM) of those organs, plays a central role in site-specific metastasis. The phenomenon of site-specific metastasis was described as early as 1889, when Paget suggested the "seed and soil" hypothesis, proposing that the newly colonized organ must be a fertile soil for tumor cells. The metastatic cells need to recognize and attach to the local ECM components and to the cells of the organ. 1,2 The local ECM can also affect tumor cell proliferation by various mechanisms, one of which is the induction of autocrine growth factors and growth factor receptors.Previously we have shown that the ability of hepatomas and breast carcinomas to metastasize to a specific organ in vivo correlated directly with the ability of the cells to survive at clonal density in vitro on ECM derived from that organ. 3 We have found that the ECM component that affected the clonal growth efficiency in hepatomas and breast cancer cell lines was heparin. 3 Our studies suggested that organ-specific proteoglycans and their glycosaminoglycan chains were responsible for the regulation of autocrine growth factors in metastatic cells. 4 The autocrine growth factors could trigger either proliferation or differentiation signals, 5 depending on the differentiated state of the tumor cells and on the ECM components present.In colorectal tumors, one of the key growth factor families regulating cell proliferation is the epidermal growth factor (EGF) family, comprising both growth factors and growth factor receptors. The number of EGF receptors on colon cancer cells correlated with increased metastasis to the liver. 6 Erb-B2, another member of EGF receptor family, was found to be amplified i...

Whole Genome Analysis of Genetic Alterations in Small DNA Samples Using Hyperbranched Strand Displacement Amplification and Array–CGH

“…Dynamically compressed ratios can be converted to actual ratios by fitting log 2 values to a power-law mathematical formula as described by Yuen et al (2002). ( (Riou et al 2001). ERBB2 amplification is also associated with high gene expression levels, as demonstrated using array-CGH and array mRNA expression analysis (Pollack et al 1999).…”

Analysis of HER2 gene amplification using Differential PCR in breast cancer patients of Isfahan Province

“…They showed that amplification-dependent HER2 overexpression is associated with an increased risk of death (P=0.01), while no relationship was found between HER2 overexpression with no amplification and the rate of mortality (P =0.54). Moreover, HER2 amplification was correlated with a higher risk of multifocal metastases (P=0.02), explaining the role of HER2 in cancer invasiveness (21). Therefore, measurement of HER2 gene amplification would be a better indicator comparing with its overexpression in breast cancer patients.…”

Isolated tumor cells in the bone marrow (ITC-BM) of breast cancer patients before and after anthracyclin based therapy: influenced by the HER2- and Topoisomerase IIα-status of the primary tumor?

“…This could be explained by methodical problems with the processing of older paraffin embedded tissue, but there is also description of transcriptional activation of the HER2 or neighbored genes which leads to protein overexpression in cases without amplification (Pauletti et al 2000). Yet, FISH analysis is recommended as the most accurate and objective method of HER2 determination nowadays, at least in IHC indeterminate cases (Bartlett et al 2003;Kakar et al 2000;Riou et al 2001).…”