Mammary-Specific Ron Receptor Overexpression Induces Highly Metastatic Mammary Tumors Associated with β-Catenin Activation

Abstract

Activated growth factor receptor tyrosine kinases (RTK) play pivotal roles in a variety of human cancers, including breast cancer. Ron, a member of the Met RTK proto-oncogene family, is overexpressed or constitutively active in 50% of human breast cancers. To define the significance of Ron overexpression and activation in vivo, we generated transgenic mice that overexpress a wild-type or constitutively active Ron receptor in the mammary epithelium. In these animals, Ron expression is significantly elevated in mammary glands and leads to a hyperplastic phenotype by 12 weeks of age. Ron overexpression is sufficient to induce mammary transformation in all transgenic animals and is associated with a high degree of metastasis, with metastatic foci detected in liver and lungs of >86% of all transgenic animals. Furthermore, we show that Ron overexpression leads to receptor phosphorylation and is associated with elevated levels of tyrosine phosphorylated B-catenin and the up-regulation of genes, including cyclin D1 and c-myc, which are associated with poor prognosis in patients with human breast cancers. These studies suggest that Ron overexpression may be a causative factor in breast tumorigenesis and provides a model to dissect the mechanism by which the Ron induces transformation and metastasis.

Regulation of RON Tyrosine Kinase-mediated Invasion of Breast Cancer Cells

“…Elevated RON expression was strongly correlated to phosphorylation and invasive activity of tumors (12), thus suggesting that increased RON expression plays a role in the progression of carcinomas to invasive-metastatic phenotypes. Mammary-specific RON receptor overexpression induced metastatic mammary tumors that has been shown to involve ␤-catenin activation (24). Our data clearly demonstrated that MSP stimulates the invasive phenotype of MDA MB 231 and MDA MB 468 breast cancer cells (Fig.…”

Modeling Metastatic Breast Cancer in Mice

“…Transgenic overexpression of Ron in MMTV-Ron mice is sufficient to induce mammary tumors that metastasize to the liver and lungs with high penetrance. In contrast to the MET RTK, activating mutations in Ron did not confer a higher tumor incidence or metastasis rate [92].…”

Alterations in a defined extracellular region of the RON receptor tyrosine kinase promote RON-mediated motile and invasive phenotypes in epithelial cells

“…RON is composed of a 45 kDa extracellular ·-chain and a 150 kDa transmembrane ß-chain linked by a disulphide bond (7). Recent studies have uncovered a previously unrecognized link between aberrant RON expression and pathogenesis of human epithelial cancers including those from breast and colon (8)(9)(10)(11). Immunohistochemical staining of primary cancer samples has revealed that RON is overexpressed at around 50% of primary breast cancer sampled with different histological subtypes (8,12).…”

“…Overexpression associates with the diseases at any stage, correlates with the post-menopausal status (8), and serves as an independent predictor of distant relapse in breast cancer patients (13). Biochemically, RON overexpression causes constitutive tyrosine phosphorylation, which stimulates downstream signaling pathways including MAP kinase and PI-3 kinase (8)(9)(10)(11). These activities lead to dramatic cellular morphological changes with increased cell migration and matrix invasion (8)(9)(10)(11).…”

“…Biochemically, RON overexpression causes constitutive tyrosine phosphorylation, which stimulates downstream signaling pathways including MAP kinase and PI-3 kinase (8)(9)(10)(11). These activities lead to dramatic cellular morphological changes with increased cell migration and matrix invasion (8)(9)(10)(11). In animal models, mammary-RON expression induces highly metastatic tumors (9,10).…”