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    Research Grants Awarded

    Diagnostic and Therapeutic Strategies Targeting the c-Myc Oncoprotein

    Study Section:
    Tumor Cell Biology I

    Scientific Abstract:
    The c-Myc oncoprotein is overexpressed in approximately 70% of human breast tumors and animal models have demonstrated the potent nature of c-Myc in driving mammary tumorigenesis. However, c-myc gene amplification is only reported in approximately 15% of breast cancer. Our research has revealed a novel mechanism that controls c-Myc protein accumulation through post-translational regulation of its turnover. We have identified two phosphorylation sites that are regulated by a complex signaling pathway, which have opposing control of c-Myc ubiquitin-mediated proteolysis. We have found that deregulation of this signaling pathway occurs in human cancer, leading to aberrant stabilization and accumulation of c-Myc. Moreover, stabilized c-Myc has altered phosphorylation that appears to increase its tumorigenic potential. Our objective is to develop tools to detect stabilized oncogenic c-Myc in breast cancer biopsies and to investigate the therapeutic potential of reversing c-Myc stabilization. We hypothesize that aberrant stabilization of c-Myc contributes to its ability to drive mammary tumorigenesis and that by targeting the signaling pathway that controls c-Myc stability, we can destabilize c-Myc, and cause tumor regression. Our specific aims are: 1) develop tools to detect the prevalence of c-Myc protein stabilization in human breast cancer; 2) investigate the tumorigenic potential of stabilized c-Myc using a unique animal model; and 3) target the signaling pathway that controls c-Myc stability as a novel approach to breast cancer therapy. Our study design is: 1) develop the use of phospho-specific antibodies to screen banked human breast tumors to investigate the frequency of c-Myc stabilization and correlate our results with tumor stage and grade; 2) use c-myc knock-in mice we have generated, which conditionally express either wild-type c-MycWT, constitutively stable c-MycT58A mutant, or constitutively unstable c-MycS62A mutant in the mammary gland to examine how c-Myc stability affects rates of tumor initiation, development, and metastasis; and 3) use a gene therapy approach and small molecule compounds to stimulate c-Myc degradation for in vivo treatment of mammary tumors. In this study, we will exploit our knowledge of c-Myc degradation to develop new diagnostic tools to detect stabilized c-Myc, which could lead to a major shift in our clinical analysis, from a simple cytogenetic description of c-myc gene amplification to a functional readout of c-Myc oncogenic expression. Our unique animal model will elucidate the biological properties of stabilized c-Myc in mammary tumorigenesis. Novel strategies to decrease c-Myc expression by targeting its degradation pathway could provide new anti-tumor agents with lower toxicity. Together, our proposed aims will facilitate the development of new diagnostic and therapeutic tools for c-Myc, which could have a major impact on the treatment and quality of life of breast cancer patients.

    Lay Abstract:
    Breast cancer is a devastating disease that arises when normal cells that should not divide start to proliferate due to the accumulation of multiple changes in genes that encode proteins involved in controlling cell function. One such protein is c-Myc. When c-Myc expression is increased in mammary tissue in mice they develop invasive breast cancer. Moreover, withdrawal of c-Myc expression in these models leads to spontaneous tumor regression, highlighting the importance of understanding the mechanisms that regulate c-Myc expression?and suggesting that c-Myc expression is a good target for new cancer therapies. The c-Myc protein is overexpressed in approximately 70% of human breast cancer biopsies and correlates with poor outcome. However, only approximately 15% of these tumors have amplification of the c-myc gene to explain the high level of c-Myc protein. Our research has revealed a new mechanism to explain the overexpression of c-Myc in breast cancer. We have shown that a highly regulated series of molecular events controls c-Myc protein turnover rates in cells. Our data suggests that this mechanism can become deregulated in cancer leading to aberrant protein stabilization and high-level accumulation of c-Myc. The objective of this research is to exploit our knowledge of how c-Myc protein stability is controlled to develop new diagnostic tools to detect stabilized c-Myc in breast cancer biopsies and to develop novel therapeutic strategies to destabilize c-Myc and stimulate tumor regression. We hypothesize that aberrant stabilization of c-Myc contributes to its ability to drive mammary tumorigenesis and that by targeting the signaling pathway that controls c-Myc stability, we can destabilize c-Myc, and cause tumor regression. To address this hypothesis we will pursue the following three specific aims: 1) develop tools to detect the prevalence of c-Myc protein stabilization in human breast cancer; 2) investigate the tumorigenic potential of stabilized c-Myc using a unique animal model; and 3) target the signaling pathway that controls c-Myc stability as a novel approach to breast cancer therapy. Our proposed research will develop the use of antibodies that detect stabilized c-Myc in breast cancer biopsies, which could lead to a major shift in our clinical analysis of breast tumors, from a simple description of c-myc gene copy number to a functional readout of c-Myc stabilization. Our unique animal model will reveal the ability of stabilized c-Myc to initiate breast cancer. Development of novel strategies to decrease c-Myc expression by targeting the pathway that controls its turnover may provide new targeted therapeutic tools for breast cancer that could reduce potentially life-threatening side effects. Together, our proposed aims will facilitate the development of new diagnostic and therapeutic tools for an important contributor to breast cancer, which could have a major impact on the treatment and quality of life of breast cancer patients.