Abstract
Metastasis is the biggest challenge in treating breast cancer, and it kills >40,000 breast cancer patients annually in the US. Aberrant expression of the RON receptor tyrosine kinase in breast tumors correlates with poor prognosis and has been shown to promote metastasis. However, the molecular mechanisms that govern how RON promotes metastasis, and how to block it, are still largely unknown. We sought to determine critical effectors of RON using a combination of mutational and pharmacologic strategies. High-throughput proteomic analysis of breast cancer cells upon activation of RON showed robust phosphorylation of ribosomal protein S6. Further analysis revealed that RON strongly signals through mTORC1/p70S6K, which is mediated predominantly by the PI3K pathway. A targeted mutation approach to modulate RON signaling validated the importance of PI3K/mTORC1 pathway for spontaneous metastasis in vivo. Finally, inhibition of mTORC1 with an FDA-approved drug, everolimus, resulted in transient shrinkage of established RON-dependent metastases, and combined blockade of mTORC1 and RON delayed progression. These studies have identified a key downstream mediator of RON-dependent metastasis in breast cancer cells and revealed that inhibition of mTORC1, or combined inhibition of mTORC1 and RON, may be effective for treatment of metastatic breast cancers with elevated expression of RON.
Highlights
Despite improvements in 5-year survival rates, breast cancer is still the second leading cause of cancer death among women. 90% of breast cancer deaths are due to the development of metastasis, which is still considered incurable even with the newest treatment options
We previously reported that aberrant expression of RON kinase and its ligand, macrophage stimulating protein (MSP), correlates with poor prognosis in breast cancer patients, portending worse metastasis-free and overall survival.[2]
We showed that overexpression of achieve our goal of discovering the critical downstream mediator either short-form RON (sfRON) or RON alone, or RON and MSP together, was (s) of RON signaling for breast cancer metastasis
Summary
Despite improvements in 5-year survival rates, breast cancer is still the second leading cause of cancer death among women. 90% of breast cancer deaths are due to the development of metastasis, which is still considered incurable even with the newest treatment options. Phosphorylation and resulted in a profound reduction of downan understanding of how RON mediates its metastatic function in stream signaling activity, regardless of the type of RON activation the context of specific cancers in vivo is largely lacking, and is a (Fig. 1e) These studies revealed that RON activation in our critical gap in successfully developing strategies to block RON experimental system reliably caused downstream activation of its signaling during metastatic progression. Candidates that changed promotes both ligand-dependent and -independent breast cancer >1.5 fold are listed, which shows rpS6 was the highest metastasis through activation of the mTORC1/p70S6K/ differentially phosphorylated protein in response to MSP stimularpS6 signaling axis. Absolute values of significantly changed proteins or phosphoproteins with >1.5 fold change in response to MSP
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