Overexpression of the RON gene in human breast carcinoma

Abstract

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.

Cross-talk between the proto-oncogenes Met and Ron

“…The presence of high amounts of receptors on the cell surface (overexpression) favors homodimerization and receptor activation (Heldin, 1995). This could explain why overexpression induces constitutive activation of Met and Ron kinases in vitro (Giordano et al, 1988b;Gaudino et al, 1994) and in several human tumors (Di Renzo et al, 1995;Natali et al, 1996;Maggiora et al, 1998;Taniguchi et al, 1998).…”

“…The antiMet monoclonal antibody (DQ13) and the anti-Ron antiserum were obtained as described elsewere (Gaudino et al, 1994;Crepaldi et al, 1994a). Recombinant HGF and MSP were obtained from baculovirus-infected SF-9 cells as previously described (Naldini et al, 1995;Maggiora et al, 1998).…”

“…Its overexpression in a signi®cant fraction of primary breast carcinomas suggests a correlation with progression of mammary tumors (Maggiora et al, 1998). The expression of both Ron and its ligand, MSP, in a number of non-small-cell lung carcinomas has been reported, suggesting that an autocrine-paracrine system may be involved in the pathogenesis of lung cancer (Willett et al, 1998).…”

Expression of protein tyrosine phosphatase alpha (RPTPα) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo

“…In breast cancer, HER2/neu overexpression is an important prognostic indicator, and constitutes a therapeutic target (Ross and Fletcher, 1999), but other receptor tyrosine kinases (RTKs) are also overexpressed (Barker et al, 1995;Ellis et al, 1998;Ghoussoub et al, 1998;Maggiora et al, 1998).…”

New tools for dissecting RON receptor tyrosine kinase oncogenic signaling

“…Overexpression of the receptor has been observed in a variety of cancers including colorectal adenocarcinomas 13 and carcinomas of the ovaries, 10 bladder 14 and breast. 15,16 In addition, ligand-independent activation of RON has been observed in various cancer samples. 13,17,18 For example, omission of the first IPT domain of RON through an aberrant mRNA splicing event which result in an in frame splice variant (RON∆160) produces a constitutively activated version of RON capable of cellular transforming activities in the absence of ligand.…”