β-Catenin is required for Ron receptor-induced mammary tumorigenesis

Abstract

Our previous studies demonstrated that selective overexpression of the Ron receptor tyrosine kinase in the murine mammary epithelium leads to mammary tumor formation. Biochemical analysis of mammary tumor lysates showed that Ron overexpression was associated with increases in β-catenin expression and tyrosine phosphorylation. β-catenin has also been shown to be regulated through tyrosine phosphorylation by the receptor tyrosine kinases Met, Fer, and Fyn. However, the molecular and physiological roles of β-catenin and β-catenin tyrosine phosphorylation downstream of Ron are not known. To investigate this association, we show that Ron and β-catenin are coordinately elevated in human breast cancers. Our data also demonstrate that activation of Ron, through ligand binding by hepatocyte growth factor-like protein (HGFL), induces the tyrosine phosphorylation of β-catenin, primarily on tyrosine residues Tyr 654 and Tyr 670. In addition, HGFL mediated Ron activation induces both β-catenin nuclear localization and transcriptional activity, with Tyr 654 and Tyr 670 residues of β-catenin being critical for these processes. We also demonstrate that a knockdown of Ron in breast cancer cell lines leads to a loss of HGFL-induced β-catenin-dependent transcriptional activation and cell growth which can rescued by activation of canonical Wnt/β-catenin signaling. Moreover, we show that HGFL-dependent Ron activation mediates upregulation of the β-catenin target genes cyclin D1 and c-myc, and that expression of these target genes in breast cancer cells is decreased following inhibition of Ron and/or β-catenin. Finally, we show that genetic ablation of β-catenin in Ron-expressing breast cancer cells decreases cellular proliferation in vitro, as well as mammary tumor growth and metastasis following orthotopic transplantation into the mammary fat pad. Together, our data suggest that β-catenin is a crucial downstream regulator of Ron receptor activation and is an important mediator of mammary tumorigenesis.

β-Catenin Signaling Is a Critical Event in ErbB2-Mediated Mammary Tumor Progression

“…6). Our observations are consistent with numerous reports where genetic ablation of b-catenin in various in vivo systems diminished metastatic progression (46,47), providing support for b-catenin as a critical mediator of the metastatic process.…”

CD151 represses mammary gland development by maintaining the niches of progenitor cells

“…42 As shown in Figure 7A, expression of Ron protein was markedly diminished in mammary tissues in the absence of CD151. In line with this observation was a marked decrease in the phosphorylation at the Y654 residue of b-catenin upon CD151 removal as described in a prior study, 42 while activation of GSK-3b, crucial for Wnt signaling, remained unaffected 43,44 (Fig. 7A).…”

Wnt Signaling in Mammary Glands: Plastic Cell Fates and Combinatorial Signaling

“…This may also explain the observation that human basaloid breast tumor aggression is associated with (and dependent on) hyperactivation of Fgf signaling (Turner et al 2010a,b;Sharpe et al 2011). Similarly, activation of the tyrosine kinase Ron has been associated with b-catenin phosphorylation (Y 654 and Y 670 ), together with enhanced nuclear translocation and transactivation activity (Wagh et al 2011). Furthermore, when a Wnt signal is present, two reports suggest that Akt activation is sufficient to activate the nuclear translocation of b-catenin, in human and mouse breast tumor epithelial cells (Korkaya et al 2009;Zhang et al 2010b).…”