Breast cancer is frequently associated with the deregulation of receptor tyrosine kinase (RTK) signaling that normally exhibits tight control over cellular processes involved in cell growth, death, differentiation, metabolism, angiogenesis, motility and invasion. The RTK known as recepteur d'origine nantais (RON) exhibits increased expression in at least 47% of human breast cancers. Furthermore, increased expression of RON and its ligand, the macrophage stimulating protein (MSP), has been correlated with a poor patient prognosis and a reduced 5-year survival rate.

It is currently not clear how RON-mediated signaling contributes to the progression of breast cancer. To address the signaling mechanisms that RON utilizes to promote oncogenic behavior in breast cancer, we generated RON-expressing MCF-10A non-transformed breast epithelial cells. In MCF-10A cells, RON signals via two alternative pathways: one that requires MSP, and one that occurs in the absence of MSP. Although MSP was necessary to promote RON-mediated proliferation and migration, RON-mediated cell adhesion, spreading, 3-D morphological changes and survival was not dependent on MSP. The intracellular tyrosine kinase Src was necessary for MSP-independent phosphorylation of RON in MCF-10A cells, and chemical inhibition of Src completely abrogated both cell spreading and survival. In addition, we found that MCF-10A/RON cells exhibited increased expression of the extracellular matrix protein hyaluronan on their surface compared to MCF-10A control cells. These data imply that MSP-independent activation of RON is potentially explained by interactions of RON with hyaluronan-activated cell surface receptors, some of which are known to influence RON signaling in other cell systems.

Taken together, the results from this study suggest that RON signaling may contribute to the development and progression of human breast cancers, even the absence of MSP.