The work funded by this DOD grant has provided a mechanistic basis for the involvement of the alpha-6 integrins in breast carcinoma progression. Our mechanistic studies substantiate several more clinical studies that have indicated the involvement of these integrins in breast cancer. The key findings are that the alpha-6 integrins are necessary for the survival of metastatic breast carcinoma cells and that they also promote the invasion of these cells. In addition, considerable progress has been made in understanding the signaling mechanisms that underlie the involvement of these integrins in migration and invasion. Future work in this area will be multi-faceted. At the basic science level, more work is needed to define the signaling pathways regulated by these integrins in breast carcinoma cells, as well as the functional association of these integrins with growth factor receptors that have been implicated in breast cancer, especially the erbB family. In addition, the hypotheses that have been generated by our work need to be validated using transgenic models of breast cancer. From a clinical perspective, the potential use of the alpha-6 integrins and associated molecules as prognostic markers for breast cancer and as potential therapeutic targets needs to be exploited.