Ron receptor signaling augments mammary tumor formation and metastasis in a murine model of breast cancer.
The tyrosine kinase receptor Ron has been implicated in several types of cancer, including overexpression in human breast cancer. This is the first report describing the effect of Ron signaling on tumorigenesis and metastasis in a mouse model of breast cancer. Mice with a targeted deletion of the Ron tyrosine kinase signaling domain (TK-/-) were crossed to mice expressing the polyoma virus middle T antigen (pMT) under the control of the mouse mammary tumor virus promoter. Both pMT-expressing wild-type control (pMT+/- TK+/+) and pMT+/- TK-/- mice developed mammary tumors and lung metastases. However, a significant decrease in mammary tumor initiation and growth was found in the pMT+/- TK-/- mice compared with controls. An examination of mammary tumors showed that there was a significant decrease in microvessel density, significantly decreased cellular proliferation, and a significant increase in terminal deoxynucleotidyl transferase-mediated nick end labeling-positive staining in mammary tumor cells from the pMT+/- TK-/- mice compared with the pMT+/- TK+/+ mice. Biochemical analyses on mammary tumor lysates showed that whereas both the pMT-expressing TK+/+ and TK-/- tumors have increased Ron expression compared with normal mammary glands, the pMT-expressing TK-/- tumors have deficits in mitogen-activated protein kinase and AKT activation. These results indicate that Ron signaling synergizes with pMT signaling to induce mammary tumor formation, growth, and metastasis. This effect may be mediated in part through the regulation of angiogenesis and through proliferative and cell survival pathways regulated by mitogen-activated protein kinase and AKT.
Peace
Belinda E
BE
Department of Surgery, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Toney-Earley
Kenya
K
Collins
Margaret H
MH
Waltz
Susan E
SE
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D007178:Inbreeding; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction
D011518:Proto-Oncogene Proteins; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt