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