Mammary-specific Ron receptor overexpression induces highly metastatic mammary tumors associated with beta-catenin activation.
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 beta-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.
Zinser
Glendon M
GM
Department of Surgery, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45267, USA.
Leonis
Mike A
MA
Toney
Kenya
K
Pathrose
Peterson
P
Thobe
Megan
M
Kader
Sarah A
SA
Peace
Belinda E
BE
Beauman
Shirelyn R
SR
Collins
Margaret H
MH
Waltz
Susan E
SE
D000818:Animals; D003001:Cloning, Molecular; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006965:Hyperplasia; D008321:Mammary Glands, Animal / Q000473:pathology / Q000502:physiology; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D000090063:Proto-Oncogene Mas; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases