The development of bone metastases is a common feature of advanced breast cancer cases. Skeletal metastases often result in pathologic bone destruction and formation, seriously weakening overall bone integrity leading to debilitating bone pain, pathological fractures, paralyzing nerve and spinal cord compressions, and metabolic imbalances that significantly diminish the quality of life of these patients. Importantly, bone metastases are incurable and treatment remains palliative. Multiple causative factors have been identified as contributors to the development of breast cancer bone metastases. Therapeutic agents targeting any single causative factor reduce bone metastasis progression but do not lead to cure. The limited success of such single targeted therapies indicates a deeper understanding of mechanisms driving the spread of breast cancer to bone is required for the future development of highly targeted and efficacious treatment modalities. Utilizing an animal model of medulloblastoma bone metastasis generated by our laboratory as a 'discovery tool', macrophage migration inhibitory factor (MIF) was identified as a factor potentially orchestrating the development of breast cancer osteolytic bone metastasis through propagation of a self-promoting feed- forward signaling loop between breast cancer and bone cells. This signaling loop is hypothesized to result in enhanced breast cancer survival and proliferation, while instigating pathological bone destruction. The current proposal aims to (1) examine if MIF modulates osteoblast and osteoclast cell survival, proliferation, and activity, and (2) determine i MIF promotes the formation of osteolytic bone lesions using an animal model of breast cancer osteolytic bone metastasis, in which MIF expression has been suppressed in cancer cells. Information obtained through completion of this proposal will provide invaluable insight into MIF-specific mechanisms of breast cancer bone metastasis that may be used in the development of targeted bone metastasis treatment modalities. Additionally, information gleaned from this work may be used in the generation of therapeutic interventions for other diseases associated with osteoclast-mediated bone loss, such as osteoporosis and diabetes-associated bone disease.

Public Health Relevance

We recently identified macrophage migration inhibitory factor (MIF) as a factor that potentially promotes the metastasis of breast cancer to bone by instigating bidirectional communication between breast cancer and bone cells. We hypothesize that this cross-talk instigates a self-promoting 'vicious cycle'of rapid breast cancer cell growth and debilitating bone loss, that results in bone pain, fractures, paralyzing nerve compressions and treatment resistance. Information gleaned from our studies will provide us with a better understanding of MIF's role in breast cancer bone metastasis, and may lead to the development of more effective therapies for this devastating disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10B-S (20))
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Sharrock, William J
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University of Alabama Birmingham
Anatomy/Cell Biology
Schools of Medicine
United States
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