Publication Date

12-2017

Date of Final Oral Examination (Defense)

8-25-2017

Type of Culminating Activity

Dissertation

Degree Title

Doctor of Philosophy Biomolecular Sciences

Department

Biology

Supervisory Committee Chair

Cheryl Jorcyk, Ph.D.

Supervisory Committee Member

Kenneth A. Cornell, Ph.D.

Supervisory Committee Member

Daniel Fologea, Ph.D.

Supervisory Committee Member

Denise G. Wingett, Ph.D.

Abstract

Breast cancer is the most diagnosed cancer type in women and its resultant mortality is second only to lung cancer worldwide. While breast cancer is known to have many risk factors, inflammation remains an unquantifiable risk, and it can arise from obesity, depression, poor health, autoimmune diseases, and other conditions that cause systemic chronic inflammation. Chronic inflammation is gaining recognition for its role in cancer development, the potentiation of a metastatic phenotype in cancer cells, and decreased survival in breast cancer patients. In particular, inflammatory cytokines in the interleukin-6 (IL-6) family have been shown to promote an epithelial-mesenchymal transition (EMT), tumor cell detachment, invasion, and metastasis. However, therapies to inhibit IL-6 have not been successful in treating solid tumors. This is most likely due to redundancy, as there are other inflammatory cytokines such as oncostatin M (OSM) and interleukin-1 beta (IL-1β) that demonstrate overlapping effects in cancer progression. In these studies, the interactions between OSM, IL-6 and IL-1β were addressed. First, OSM and IL-6 were shown to induce vascular endothelial growth factor (VEGF) in a breast cancer subtype-specific manner. Next, OSM was assessed for its capacity to increase circulating tumor cell numbers in mouse models of human breast cancer. Lastly, OSM, IL-6, and IL-1β expression levels were shown to correlate with each other in breast cancer, and high co-expression of these cytokines was shown to lead to decreased patient survival. Furthermore, OSM was assessed for its synergistic relationship with IL-1β in inducing IL-6 secretion from breast cancer cells. Together, these results suggest that inflammatory cytokines promote metastatic disease in a breast cancer subtype-dependent manner. Importantly, these studies both provide a rationale for the development of breast cancer therapeutic regimens that target multiple cytokines as well as help explain why single anti-cytokine therapies have failed in clinical trials.

DOI

https://doi.org/10.18122/B28H9P

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