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    Awarded Grants
    Significance of Shc-dependent Signaling Pathways in Breast Cancer Angiogenesis

    Scientific Abstract:
    Background: Solid tumors and metastasis remain microscopic if angiogenesis, the formation of new blood vessels, is not induced to supply oxygen and nutrients. Angiogenesis of human breast cancers is often associated with elevation of pro-angiogenic factors (vascular endothelial growth factor, VEGF) and a decrease of inhibitors of angiogenesis (thrombospondin-1, TSP-1). The HER2 and Met/Hepatocyte growth factor (HGF) receptor tyrosine kinases (RTK) contribute to tumor vascularization by regulating VEGF and TSP-1. Significantly, tumor regression observed by breast cancer therapies targeting HER2, like Herceptin™, has been in part attributed to anti-angiogenic activities. We have recently identified that the Shc adapter protein is critical for the induction of VEGF and downmodulation of TSP-1 downstream from HER2 and Met/HGF receptors. Rational/Hypothesis: Based on the strict dependence of breast tumors on neovascularization for progression, and that all RTKs deregulated in human breast cancers, can engage Shc signals, we hypothesize that Shc is a key regulator of breast cancer angiogenesis. Objective: This proposal will address the role of Shc as a key regulator of angiogenesis in human breast cancers. Specific aims: I) Define the Incidence of Shc Engagement vs. Angiogenic Profile in Human Breast Cancers. This will be evaluated on a representative cohort of frozen sections of human breast cancer (300) and matched normal tissues using an immunohistochemistry based approach. Shc engagement will be assessed using antibodies that recognize phosphorylated Shc, and will be correlated by multivariant ananlyses with Shc levels, and the angiogenic profile of the tumor and the stroma using Anti-CD31, as well as with anti-VEGF or anti-TSP-1. II) Investigate the Therapeutic Significance of Shc in Breast Cancer Angiogenesis. We will develop RNAi and anti-sense oligonucleotide strategies to deplete Shc. The angiogenic and tumorigenic potential of cells exhibiting a Shc knockdown will be tested in vivo, and the ability of circulating Shc anti-sense oligonucleotides to inhibit/decrease angiogenesis and growth of breast tumor xenografts will be evaluated. III) Identify the Signaling Pathways Downstream of Shc Required for Tumor Angiogenesis. Structure function analyses will be performed to define protein interaction domain(s) of Shc required for VEGF production and TSP-1 inhibition. Relevance: This proposal will define the scope and therapeutic significance of Shc as a master regulator of both positive (VEGF) and negative (TSP-1), and of angiogenesis in human breast cancers.

    Lay Abstract:
    Background: Breast cancers arise through accumulation of multiple changes in cells. These may never be fully understood since they can vary in every tumor. Thus one of the challenges in the development of new cancer therapies is to identify targets that regulate key tumor processes. Cancer cells, as well as normal cells in the body, need oxygen and nutrients supplied by surrounding blood vessels to survive. Breast tumors will not grow unless new blood vessels are formed. In contrast to normal blood vessels, these formed within tumors are usually leaky. This provides an escape route for tumor cells to enter the blood stream and to travel to distant sites in the body where they may grow as metastases. Up to 40% of breast cancers show alterations of cell surface molecules (growth factor receptors), such as HER2 and others (EGFR, HGFR) that regulate a variety of biological processes, including the formation of new blood vessels, a process named angiogenesis. We have shown that HER2, as well as other receptors, induce an angiogenic response through a molecule called Shc. Importantly, we have demonstrated that Shc regulates both positive and negative signals for the formation of tumor blood vessels. Shc activates positive signals (VEGF) and inhibits negative signals (Thrombospondin). Thus, Shc represents a potentially novel therapeutic target to fight breast cancer. Rational/Hypothesis: Based on the knowledge that progression of breast cancers is dependent on angiogenesis and that the alteration of receptors that regulate Shc is common in breast cancers, we hypothesize that Shc signals provide an advantage for the progression of breast cancer by promoting the formation of new blood vessels. Specific Aims: We propose to 1) test whether Shc is a prognostic marker for breast cancer angiogenesis and progression, 2) determine if Shc is a valid target for development of anti-angiogenic therapy for breast cancer, and 3) define the mechanism through which Shc regulates angiogenesis. Research Outcome: Cancer drugs to individual angiogenic factors, such as VEGF, have shown promise in clinical trials, but these are not sustained as tumor cells can utilize other angiogenic promoting molecules that are not inhibited by these therapies. Our data hypothesizes that Shc will act as a general target for tumor angiogenesis induced by growth factor receptors. The understanding of the scope and significance of Shc in breast cancer angiogenesis, obtained upon the completion of this proposal, will provide a rational for the development of new and more efficient anti-angiogenic therapies.