All ETDs from UAB

Advisory Committee Chair

Xu Feng

Advisory Committee Members

Joanna Murphy-Ullrich

Andra Frost

Kurt Zinn

Richard Lopez

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The molecular mechanisms regulating the preferential metastasis of breast cancer to bone have not been fully elucidated, but it is hypothesized that local conditions in the bone create an environment conducive to colonization by breast cancer cells and that the breast cancer cells interact directly with cells in the bone. In this dissertation, two goals were pursued: (1) to explore breast cancer secreted interleukin (IL)-11's role on osteoclast function and (2) investigate the expression and potential role of CD68 in breast cancer adhesion to bone. Higher rates of bone metastasis occur in human breast cancer tumors expressing IL-11, a cytokine shown to promote osteoclast formation, but the specific mechanisms are controversial. I determined that breast cancer secreted IL-11 was unable to directly support osteoclast survival or formation in sub-optimal RANKL conditions but instead supports a population of osteoclast progenitors. These findings clarify IL-11's specific role in breast cancer bone metastasis, and future studies are warranted to address the therapeutic potential of IL-11 for treating and preventing breast cancer induced osteolysis. For the second aim, I examined breast cancer cell lines and found that CD68, a lysosomal associated membrane protein associated with breast cancer recurrence, is upregulated in breast cancer lines that have a high capacity to metastasize to bone. A fragment of CD68 was independently identified in a phage display assay to pan for bone adhesion molecules, suggesting CD68 may be involved in breast cancer bone metastasis by acting as a bone adhesion molecule. Expression of CD68 correlated with ability of breast cancer cell lines to adhere to bone, but more specific assays failed to reveal a direct role of CD68 in adhesion to bone. Future studies are needed to characterize CD68's exact role in breast cancer, but the discovery of breast cancer expression may have implications for the common use of CD68 as a macrophage marker, and may provide insight into CD68's correlation as a risk factor for breast cancer recurrence. These studies contribute to the foundation of work necessary for developing specific therapeutics by contributing to a better understanding of the mechanisms regulating breast cancer bone metastasis.

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