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

• Published in: Endocrinology (Philadelphia) Vol. 153; no. 6; pp. 2735 - 2746
• Main Authors: Wagh, Purnima K, Zinser, Glendon M, Gray, Jerilyn K, Shrestha, Archana, Waltz, Susan E
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01.06.2012
• Subjects: Animals; beta Catenin - deficiency; beta Catenin - genetics; Biological and medical sciences; Blotting, Western; Cell Transformation, Neoplastic - genetics; Cyclin D1 - genetics; Cyclin D1 - metabolism; Epithelial Cells - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Growth Factors-Cytokines; Hyperplasia; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Male; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Knockout; Mice, Transgenic; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Vertebrates: endocrinology; Vertebrata; Mammalia; Mouse; Animal; Rodentia; Deletion; Epithelial cell; Catenin; Biological receptor
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2011-1543

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 β-catenin and β-catenin target genes. β-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 β-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 β-catenin in the context of Ron overexpression, we conditionally deleted β-catenin in mammary epithelial cells of MMTV-Ron mice. Conditional deletion of β-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. β-Catenin loss in this model was also associated with decreased expression of cyclin D1. In total, these studies support an important role for β-catenin downstream of Ron receptor signaling during the development of mammary tumorigenesis.