This application is a competing renewal of R01 CA84360 previously entitled """"""""The Metalloproteinase Matrilysin in Breast Cancer"""""""". The title is changed to """"""""Tumor and Stromal MMPs in Breast Cancer"""""""" to reflect an expansion of the focus of the application from the role of MMP-7 (matrilysin) in early stage breast cancer to the role of both tumor and stromal MMP family members in the processes of breast metastasis to lung and bone. The clinical experience with MMP inhibitors over the past few years indicates these agents are ineffective in controlling the progression of advanced stage cancer. However, an NCI-sponsored workshop recently concluded that MMP inhibition represents a therapeutic opportunity for minimal residual disease and bone metastases. Thus, we have changed the focus of this grant to concentrate on the clinically relevant problems of breast cancer metastasis to lung and bone with the goal of increasing our understanding of the MMP contribution to these processes with preventive or therapeutic endpoints in mind. Using an MMTV-polyoma middle T antigen (PyVT) transgenic mouse system, we demonstrated that the lack of MMP-7 and MMP-9 has no impact on the development of primary mammary tumors, but MMP-9 deficiency reduces the development of lung metastases. Tumor-associated MMPs can be either tumor or stromal in origin. We have determined that host-derived MMP-9 is required for efficient establishment of lung metastases following tail vein injection of lung carcinoma cells. Our working hypothesis is that MMPs contribute to breast cancer metastasis to lung and bone by mediating tumor/stroma interactions. We propose to examine the contribution of tumor and stromal MMPs to: 1) the dormancy, development, and growth of breast metastases in lung, and 2) the growth and lytic activity of breast metastases in bone using syngeneic mouse model systems of MMTV-PyVT-derived mammary tumor cells placed in the lung or bone microenvironment. The molecular mechanisms underlying the effect of tumor or stromal MMPs will be probed using organotypic co-culture models of lung and bone and both candidate and unbiased proteomic approaches to identify relevant MMP substrates. These studies will provide guidance for the application of synthetic MMP inhibitors for the prevention and treatment of breast cancer metastasis.
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