Angiogenesis and tumor metastasis require changes in expression of a large number of genes in multiple cell types. Increased angiogenic and metastatic potential in tumor cells most likely results from coordinated changes in expression of banks of genes. At present, little is known about which and how signaling pathway(s) regulates coordinated expression of these gene banks. We hypothesis that phosphatidylinositol-3-kinase (P13-K) and/or downstream signaling intermediates are key regulators of genes involved in early steps of angiogenesis and metastasis. To test this hypothesis, we have developed the following Specific Aims: (I) Analysis of the metastatic and non- metastatic tumor lines in a murine mammary tumor model for differences in both P13-K-related and PyMT-proximal signal transduction pathways, (II) In vitro analysis of metastatic and non-metastatic tumor lines with disrupted P13-K activation pathways, and (III) In vivo analysis of metastatic and non-metastatic tumor lines with disrupted P13-K activation pathways. This proposal is directly relevant to human interpretation since c-erb-2 and other receptor tyrosine kinases implicated in human breast cancer interact with P13-K. Because little is known about signaling pathways in angiogenesis and metastasis, results from this study will fill important gaps in our understanding of the disease process(es). Our results will be important for the design of new diagnostic and therapeutic modalities in human breast cancer.
