In spite of improved screening and detection methods, the five-year survival rate for female breast cancer patients with distant metastases lingers at a dismal twenty-three percent. While it is known that the extracellular matrix (ECM) plays an important role in promoting tumor growth and metastasis, clarifying how the cytokine oncostatin M (OSM) modulates changes in the tumor cell-ECM relationship is essential if anti-OSM therapeutics are to be developed for patients with metastatic breast cancer. OSM is a pleiotropic interleukin-6 (IL-6) cytokine important in inflammation and produced by activated T-cells, monocytes/macrophages, neutrophils, and human breast cancer cells. Our recently published data demonstrates that OSM induces osteolytic bone metastases in vivo and osteoclast differentiation/activity in vitro, implicating OSM as an important factor in the localized bone metastatic microenvironment. We have also shown that OSM promotes breast cancer cell detachment and invasive capacity in vitro, indicating the importance of OSM in the tumor cell-ECM matrix interaction. Finally, our unpublished data shows that OSM increases lung metastases in vivo, suggesting that this cytokine may be a key factor driving breast cancer invasion and metastasis to vital organs. Therefore, we hypothesize that OSM promotes breast tumor cell-ECM disruption resulting in invasion and metastasis. To test our hypothesis, we propose two specific aims: 1) Demonstrate that OSM is critical for disrupting the breast tumor cell-ECM interaction during invasion and metastasis and 2) Determine the mechanism by which OSM-induced proteases promote invasion. In the first aim, tumor progression, endpoint metastases, survival, and tumor-produced protease expression induced by OSM will be evaluated in an inducible-OSM expression orthotopic xenograft model of breast cancer. In the second aim, proteases involved in OSM-promoted invasion such as cathepsins D and B will be evaluated. Both 2D cultures and novel 3D Mammary Architecture and Microenvironment Engineering (MAME) models will provide information on protease secretion in real time. These studies will advance our understanding of cytokine-promoted ECM control on breast cancer metastasis. This work, through the Boise State University COBRE in Matrix Biology, along with the help and collaboration of a scientific mentor, Dr. Bonnie Sloane, will lead to the development of a grant proposal to be submitted for R01 funding.
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