Conditional Deletion of β-Catenin in Mammary Epithelial Cells of Ron Receptor, Mst1r, Overexpressing Mice Alters Mammary Tumorigenesis

Abstract

The Ron receptor tyrosine kinase (macrophage stimulating 1 receptor) is overexpressed in approximately 50% of human breast cancers. Transgenic mice overexpressing Ron in the mammary epithelium [mouse mammary tumor virus driven (MMTV)-Ron expressing mice] develop mammary tumors that exhibit up-regulation of ␤-catenin and ␤-catenin target genes. ␤-Catenin has been shown to be a mediator of mammary tumorigenesis in various breast cancer models, including downstream of Ron. However, the in vivo impact of a conditional loss of ␤-catenin downstream of Ron receptor overexpression on the onset, growth, turnover, and metastasis of mammary tumors has not been addressed. To determine the significance of ␤-catenin in the context of Ron overexpression, we conditionally deleted ␤-catenin in mammary epithelial cells of MMTV-Ron mice. Conditional deletion of ␤-catenin in the mammary epithelium, through the use of whey acidic protein (WAP)-Cre transgenic mice, significantly delayed the onset of mammary hyperplastic nodules, the presence of palpable mammary tumors, and ultimately decreased liver metastasis. ␤-Catenin loss in this model was also associated with decreased expression of cyclin D1. In total, these studies support an important role for ␤-catenin downstream of Ron receptor signaling during the development of mammary tumorigenesis. (Endocrinology 153: 2735-2746, 2012)

Ron receptor tyrosine kinase signaling as a therapeutic target

“…This is an HGFL dependent event whereby activation of Ron by ligand stimulation leads to β-catenin nuclear localization and subsequent increases in c-myc and cyclin D1 [42]. Further, we demonstrated the important requirement for β-catenin in mammary tumorigenesis, as loss of β-catenin leads to a delay in mammary hyperplasia and reduced the metastatic burden in mice that overexpress Ron in the mammary epithelium [43]. Additionally, work in the prostate has supported the role of Ron in β-catenin activation where overexpression of Ron leads to accumulation of β-catenin protein and increased pErk [44].…”

Vitamin D3-dependent VDR signaling delays ron-mediated breast tumorigenesis through suppression of β-catenin activity

“…Activation of β-catenin can occur directly through Ron-induced phosphorylation of residues Tyr 654 and Try 670 resulting in β-catenin nuclear translocation and enhanced transcription of cyclin D1 and c-Myc target genes [ 14 ]. Moreover, genetic ablation of β-catenin reduced Ron-directed mammary tumor growth and metastasis, as well as cell proliferation in vitro [ 14 ], which was further confirmed in a study utilizing a transgenic mouse model with Ron overexpression in the mammary epithelium and targeted deletion of β-catenin [ 21 ]. Thus, understanding how perturbations in the Ron-β-catenin signaling axis affect the therapeutic response of breast cancers with a highly metastatic phenotype is critical for lessening the deaths associated with metastatic disease.…”

RON Signaling Is a Key Mediator of Tumor Progression in Many Human Cancers

“…Expression analysis of molecules involved in cell cycle progression revealed that RON overexpression led to increased phosphorylation of MAPK and b-catenin, and up-regulation of bcatenin target genes such as cyclin D1 and c-Myc (Zinser et al 2006). Conditional deletion of b-catenin in the context of RON overexpression resulted in delayed onset of mammary hyperplastic nodules and tumorigenesis, decreased tumor growth, and decreased liver metastasis at the studied time point, revealing a contributing, but not essential, role of b-catenin in mammary tumorigenesis downstream from RON (Wagh et al 2012). Gene expression analysis of the A2780 ovarian cell line has shown upregulation of several MAPK target genes in response to MSP (Chaudhuri et al 2011).…”