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Understanding the Mechanisms Through Which Matrix Metalloproteinases (MMPs) Contribute to Breast Cancer-Associated Osteolytic Lesions
Annual summary rept. 15 Feb 2006-14 Feb 2009
VANDERBILT UNIV MEDICAL CENTER NASHVILLE TN
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Bone metastasis is a common event during breast cancer BC progression. Matrix Metalloproteinases MMPs are often overexpressed in BC and play an important role in tumor progression. Metastatic BC is primarly osteolytic and we hypothesize that specific host derived MMPs contribute to the growth and development of osteolytic lesions. In an intratibial model that recapitulates breast induced osteolysis, we demonstrated that host MMP-2 and MMP-7 are required for mammary tumor growth in the bone and the development of osteolytic lesions. However MMP-9 does not affect tumor growth and bone resorption in our model of mammary tumor-associated bone lesions. Osteoclast-derived MMP-7 mediates its effect through the processing of RANKL into its soluble form which increases osteoclast precursor cell recruitment and activation. Osteoblast-derived MMP-2 impacts mammary tumor survival in the bone microenvironment by controlling levels of active TGF-beta via the processing of its latency protein, LTBP-3, novel substrate for MMP-2. In conclusion, drugs targeting specifically MMP-2 and MMP-7 could be used in combination with currently used therapies to improve treatment of BC-associated with osteolytic lesions.
APPROVED FOR PUBLIC RELEASE