Date of Final Oral Examination (Defense)

5-2011

Type of Culminating Activity

Thesis

Degree Title

Master of Science in Biology

Department

Biology

Major Advisor

Cheryl L. Jorcyk, Ph.D.

Abstract

Breast cancer is the most diagnosed cancer in women and is the second most common cancer-related death for women worldwide. While the primary tumor itself is not lethal, the metastases that disrupt vital organ functions pose a significant clinical challenge. Seventy percent of women with metastatic breast cancer have metastases to the bone, which is the most significant cause of morbidity for these patients. Oncostatin M (OSM) is a pleiotropic cytokine that plays a role in the immune system, wound repair, and haematopoiesis. OSM was previously considered for anticancer therapy due to its anti-proliferative effects against breast cancer cells in vitro. However, recent studies in the literature and from our lab suggest that OSM increases the metastatic potential of breast cancer cells. OSM has been shown to increase angiogenesis through the induction of VEGF and invasion through the release of MMP family of proteases. However, the exact role that OSM has on the metastatic cascade of breast cancer remains unclear. In this study, we attempted to elucidate the role of OSM on breast cancer metastases in an in vivo and in an in vitro mouse model of breast cancer. The results indicate that OSM increases pro-metastatic characteristics on 4T1.2 murine mammary cancer cells in vitro. OSM induced detachment and various factors that are thought to promote metastases and bone degredation such as VEGF, COX-2, IL-6, and HIF1α;. In an in vivo orthotopic 4T1.2 mouse model of breast cancer, OSM also increased the metastatic burden to the lung, spleen and the liver in vivo, while tumor growth was unaffected. In an in vitro co-culture model of the metastatic bone microenvironment, OSM and murine mammary cancer cells synergistically increased osteoclast differentiation and activity. Furthermore, inhibition of VEGF, COX-2, IL-6, or HIF1α; attenuates osteoclast differentiation. Our data suggest that OSM might be a useful target for individualized anticancer therapies on cancer patients with high level of serum OSM concentrations and may help prevent metastases and bone destruction in breast.

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