Research Project
9965610
PROJECT SUMMARY Despite new drugs and improved detection methods, the five-year survival rate for female breast cancer patients with distant metastases lingers at a dismal 27%. This is in part due to a critical lack of therapeutics specifically targeting triple negative breast cancer (TNBC), which is estrogen receptor-negative (ER-) progesterone receptor- negative (PR-) and HER2-negative (HER2-). This negative receptor status eliminates many therapeutic options that exist for ER+ PR+ HER2+ patients. Our long-term goal is to provide preventative and therapeutic treatment options for patients with metastatic breast cancer by identifying novel targeted interventions against the OSM/OSM receptor (OSMR) axis. The goal of this proposal determine how ER status contributes to OSM- induced IL-6 and OSM-promoted breast tumor invasion and metastasis. OSM is an interleukin-6 (IL-6) family cytokine important in inflammation, which is produced by activated T-cells, monocytes/macrophages, neutrophils, and human breast cancer cells. Our published data demonstrates that OSM induces osteolytic bone metastases in vivo, implicating OSM as an important factor in the localized bone metastatic microenvironment. Published data from our lab and others show that OSM promotes an epithelial-mesenchymal transition, tumor cell detachment, and an invasive phenotype in vitro, suggesting that this cytokine may be a critical factor driving breast cancer invasion and tumor cell dissemination. We have recently shown that OSM increases circulating tumor cell (CTC) numbers and metastases to lung in vivo, consistent with a more general role for OSM in metastasis. For this proposal, we hypothesize that OSM-induced IL-6 expression is dependent on a negative estrogen receptor alpha (ER?) status and that the presence of ER? will decrease OSM-driven breast cancer metastasis. To test our hypothesis, we propose two specific aims: 1) Determine the mechanisms by which ER? represses OSM-induced IL-6 expression, and 2) Analyze OSM and OSM-induced IL-6 and metastatic potential in ER+ and ER- breast cancer models. In the first aim, OSM-induced IL-6 production will be investigated in both parental and genetically modified ER+ and ER- human breast tumor cells, and the mechanisms by which ER represses OSM-induced IL-6 production will be investigated. In the second aim, genetically manipulated ER+ and ER- breast tumor mouse models will be studied with the presence or absence of OSM and Siltuximab, a neutralizing monoclonal antibody against IL-6. Together, these studies will both clarify the complex association between OSM-induced IL-6 and ER status as well as help define the patent population that will most benefit from anti-OSM therapeutics.
