The Role of ADAM9 in Tumor-Stromal Interactions in Breast Cancer

This final report covers the three years of work on the Statement of Work with particular focus on the third year of research. This report covers the major accomplishments of this research, including the development of reagents to detect the secreted form of ADAM9, the development of a model system to investigate the isoforms of ADAM-9 in breast cancer cell migration, and the use of this model system to discover novel functions for both isoforms of ADAM9. We have confirmed the presence of the secreted form of ADAM9, ADAM9-S in breast cancer cell lines and tumor lysates,. We have also confirmed the role of ADAM9-S in promoting breast cancer cell migration and shown that this is through the proteolytic function of the protein. In addition, we have shown that the alternatively spliced, membrane-bound isoform of ADAM9, ADAM9-L, suppresses cell migration in a proteolysis-independent manner. These differences are significant as ADAM9 has been identified as a druggable target for breast cancer, and the potential side-effects of an ADAM9 inhibitor will depend on the functional domain targeted and isoform prevalence in disease.