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 (ERα) status and that the presence of ERα will decrease OSM-driven
breast cancer metastasis. To test our hypothesis, we propose two specific aims: 1) Determine the mechanisms
by which ERα 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.