Oncostatin M-induced VEGF in human breast cancer is HIF1a-mediated

DESCRIPTION (provided by applicant): The purpose of this study is to investigate the mechanisms by which oncostatin M (OSM) promotes vascular endothelial cell growth factor (VEGF) in human breast cancer. Oncostatin M is a member of the interleukin-6 (IL-6) family of cytokines and is produced by many immune cells and some tumor cells. Preliminary studies on human breast cancer cells indicate that OSM promotes expression of the potent proangiogenic factor VEGF. OSM also induces expression of the alpha subunit of hypoxia-inducible factor 1 (HIF1), a critical transcription factor for VEGF gene regulation. Our recent data and other published studies suggest that OSM may promote angiogenesis, tumor progression, and metastasis in vivo. In this grant, we propose to determine the multiple mechanisms by which OSM promotes VEGF expression in human breast cancer. To accomplish this, we will investigate OSM's induction of HIF11 in breast cancer cells and other cell types and confirm that OSM-induced VEGF expression is dependent on HIF11. Additionally, we will study the mechanism behind and the signaling pathway utilized by OSM to induce HIF11. We will also determine why, in contrast to OSM, another IL-6 family cytokine, leukemia inhibitory factor (LIF), induces HIF11 but does not promote VEGF expression. Results demonstrating that OSM activates multiple pathways to upregulate VEGF would provide insight into cytokine-induced angiogenesis in tumor cells and supply rationale for the design of breast cancer therapies that inhibit OSM expression, function, or signaling. The potential to develop experimental anti-OSM therapeutics is limitless: to date, there has been no attempt to inhibit OSM for the purpose of cancer therapy. PUBLIC HEALTH RELEVANCE: The proposed work could establish an important role for oncostatin M (OSM) in breast cancer progression and metastasis. This research could provide the rationale for the development breast cancer therapeutics that target OSM to prevent metastatic spread of the disease. In addition, this project represents the opportunity for undergraduate students at Boise State University to participate in biomedical research and gain a deeper understanding of the molecular and cellular events involved in breast cancer.