Expression and loss of heterozygosity of c‐met proto‐oncogene in primary breast cancer

Nagy, János; Clark, James S.; Cooke, Alexander; Campbell, Ailsa M.; Connor, J. M.; Purushotham, Arnie; George, W.D.

doi:10.1002/jso.2930600206

Cited by 11 publications

(7 citation statements)

References 31 publications

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“…Interestingly, in these cell lines the expression of Ron inversely correlates with the expression of Met (Stoker et al, 1987;Byers et al, 1994). The data suggesting a role for Met/HGF complex in breast cancer progression are con¯icting (Yamashita et al, 1994;Nagy et al, 1995;Lin et al, 1996;Tuck et al, 1996). Here, we show that another member of the MET family, with similar biological properties, is overexpressed in a large percentage of breast carcinomas.…”

Section: Discussionmentioning

confidence: 94%

Overexpression of the RON gene in human breast carcinoma

et al. 1998

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Constitutive activation of the RON gene, known to code for the tyrosine-kinase receptor for Macrophage Stimulating Protein (also known as Scatter Factor 2), has been shown to induce invasive-metastatic phenotype in vitro. As yet, nothing is known about the expression of this novel member of the MET-oncogene family in spontaneously occurring human cancers. Here we report that Ron is expressed at abnormally high levels in about 50% primary breast carcinomas (35/74 patients). Among these, the expression is increased more than 20-fold in 12 cases and the overexpressed protein is constitutively phosphorylated on tyrosine residues. Notably, Ron is only barely detectable in epithelial cells of the mammary gland, and its expression remains unchanged in benign breast lesions (including adenomas and papillomas). Overexpression was observed in di erent histotypic variants of carcinomas; it is associated with the disease at any stage and correlates with the post-menopausal status. In breast carcinoma cells grown in vitro, activation of the Ron receptor resulted in proliferation, migration and invasion through reconstituted basement membranes. Altogether, these data suggest a role for the RON gene in progression of human breast carcinomas to the invasive-metastatic phenotype.

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Section: Discussionmentioning

confidence: 94%

Overexpression of the RON gene in human breast carcinoma

et al. 1998

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“…The data were normalized and weighted using intensity values (see Materials and Methods). All graphs show the intensity level (2–253) on the x‐axis whereas the y‐axis shows the number of pixels (pc) for each intensity level ( C,I,O,U ), calculated normalized (npc) value ( D, J, P,V ), intensity‐weighted normalized (I*npc) values ( E,K,Q,W ), and square intensity‐weighted normalized (i 2 *npc) values ( F,L,R,X ).…”

Section: Resultsmentioning

confidence: 99%

“…Hepatocyte growth factor/scatter factor (HGF/SF), the ligand for Met, is a paracrine pleiotropic factor that can act as a mitogen, morphogen, or motogen for a variety of cells. Met and HGF/SF have been implicated in breast cancer (6–9). Several studies have shown that expression of Met is a strong independent prognostic factor in breast carcinoma (10, 11).…”

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confidence: 99%

Algorithms for quantitation of protein expression variation in normal versus tumor tissue as a prognostic factor in cancer: Met oncogene expression, and breast cancer as a model

et al. 2000

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Background Immunohistochemistry and immunofluorescence (IF) assays frequently rely on subjective observer evaluation for grading. The aim of our study was to develop an objective quantitative index based on confocal laser scanning microscopy (CLSM) and image analysis of an IF assay to determine alteration in protein expression levels in normal versus tumor tissue. The relative levels of Met expression, a prognostic factor in breast cancer, were used as a model for evaluating image analysis algorithms. Methods Primary human breast cancer biopsies were collected. Sections containing tumor and adjacent uninvolved normal regions were immunostained for Met and digital images were acquired by CLSM. Subsequently, the digital data were manipulated using several different algorithms to calculate prognostic indexes. The results were correlated with the clinical outcome to determine the prognostic value of these indexes. Results Different algorithms were used to obtain quantitative indexes to evaluate the relative levels of Met expression. We report a statistical correlation between patient prognosis and relative Met level in normal versus tumor tissue as determined by three distinct algorithms using Kaplan‐Meier analysis (log‐rank): calculations based on intensity levels differences DV (P = 0.002), DIntensity (P = 0.014), and entropy divergence (Dentropy; P = 0.0023). Conclusions Using adjacent normal tissue as an internal reference, a quantitative index of tumor Met level divergence can be objectively determined to have a prognostic value. Moreover, this methodology can be used for other proteins in a variety of different diseases. Cytometry 41:155–165, 2000 © 2000 Wiley‐Liss, Inc.

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“…We have shown that Met is expressed and activated in normal breast ducts and reduced in some breast tumors (Tsarfaty et al, 1992). On the other hand, Met expression levels were shown to be signi®cantly greater for patients with breast cancer than in benign breast disease (Nagy et al, 1995). Transgenic expression of tpr-met led to development of mammary hyperplasia and tumors (Liang et al, 1996).…”

Section: Introductionmentioning

confidence: 96%

Dominant negative Met reduces tumorigenicity-metastasis and increases tubule formation in mammary cells

et al. 2000

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Activation of the Met tyrosine kinase growth factor receptor by its ligand HGF/SF has been shown to increase in vitro invasiveness in epithelial cell lines. To study the eect of Met-HGF/SF signaling in breast cancer cells, we transfected met, hgf/sf and dominant negative (DN) forms of met into the poorly dierentiated metastatic murine mammary adenocarcinoma cell line DA3. These cells express moderate levels of endogenous Met, which is rapidly phosphorylated in response to HGF/SF treatment. Met+hgf/sf transfection results in signi®cantly increased tumorigenic and metastatic activity in vivo accompanied by reduced tubule formation. DA3 cells transfected with DN forms of Met (DN-DA3) exhibit reduced Met phosphorylation following exposure to HGF/SF. Furthermore, as compared to the parental cells, the DN-DA3 cells exhibit diminished in vitro scattering and invasiveness, while in vivo they display greatly reduced tumorigenicity and spontaneous metastasis. Tumors emanating from DN-DA3 cells injected to BALB/C mice are highly dierentiated and display extensive tubule formation. These results suggest that Met-HGF/SF signaling is a determining factor in the delicate balance between dierentiation/tubule formation and tumorigenicity-metastasis.

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Expression and loss of heterozygosity of c‐met proto‐oncogene in primary breast cancer

Cited by 11 publications

References 31 publications

Overexpression of the RON gene in human breast carcinoma

Overexpression of the RON gene in human breast carcinoma

Algorithms for quantitation of protein expression variation in normal versus tumor tissue as a prognostic factor in cancer: Met oncogene expression, and breast cancer as a model

Dominant negative Met reduces tumorigenicity-metastasis and increases tubule formation in mammary cells

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