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Updated: Feb 2, 2026
An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis
Published on: August 14, 2016
mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential
Najme Faham1, Ling Zhao1, Alana L Welm1
1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT USA.
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.
Insights
Targeting the RON receptor tyrosine kinase pathway with mTORC1 inhibitors, like everolimus, may treat metastatic breast cancer. Blocking mTORC1 and RON together shows promise for halting cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Metastasis remains a significant challenge in breast cancer treatment, often linked to poor prognosis.
- Aberrant expression of the RON receptor tyrosine kinase (RTK) in breast tumors is associated with increased metastasis.
- The precise molecular mechanisms by which RON promotes metastasis and potential therapeutic targets are not fully understood.
Purpose of the Study:
- To identify critical downstream effectors of RON signaling in breast cancer.
- To investigate the role of the PI3K/mTORC1 pathway in RON-mediated metastasis.
- To evaluate the therapeutic potential of inhibiting mTORC1 and/or RON in metastatic breast cancer.
Main Methods:
- High-throughput proteomic analysis of breast cancer cells activated for RON.
- Utilized mutational strategies to modulate RON signaling.
- Employed in vivo metastasis models and pharmacologic inhibition with everolimus.
Main Results:
- Activation of RON robustly phosphorylates ribosomal protein S6, indicating signaling through mTORC1/p70S6K.
- The PI3K pathway is a predominant mediator of RON signaling to mTORC1.
- Inhibition of mTORC1 with everolimus caused transient shrinkage of RON-dependent metastases.
- Combined blockade of mTORC1 and RON delayed tumor progression in vivo.
Conclusions:
- The PI3K/mTORC1 pathway is a critical mediator of RON-driven breast cancer metastasis.
- Inhibition of mTORC1, alone or in combination with RON blockade, represents a potential therapeutic strategy for metastatic breast cancer with elevated RON expression.
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