Wound Response Genes in Cancer Progression

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DESCRIPTION (provided by applicant): The human body has a tremendous capacity for healing, but the ability of cells to grow, regenerate tissues, and recruit new blood vessels may also be misused during cancer progression. In many common cancers, especially breast cancer, the ability of tumors to express genes seen normally in a model of wound response is a powerful and accurate predictor of subsequent metastasis. We discovered that specific genetic mutations in human breast tumors drive expression of the wound response signature. Amplification of two genes, CSN5 and MYC, activate the wound response signature and causes increased cell division and invasion. CSN5 activates the post-translational modification of the MYC oncoprotein by ubiquitin, leading to activation of MYC's activity. However, molecular mechanisms of wound signature activation as well as its pathogenic mechanisms in cancer progression vivo are unclear. Therefore, we propose to study how CSN5 and MYC activate the wound signature and breast cancer metastasis in two aims. Firstly, we will determine which enzymatic activities of CSN5 and its associated COP9 complex are important for CSN5 to activate MYC and enhance tumor progression in vivo. An isopeptidase activity of CSN5 is highly amenable to inhibition by small molecule drugs and therefore could present an attractive therapeutic target in breast cancer. Secondly, we will determine how CSN5 selects between two antagonistic ubiquitin ligase pathways to activate MYC. These studies will elucidate a novel pathway implicated in breast cancer progression and pinpoint specific targets for therapeutic intervention. Breast cancer is the second most common cause of cancer death for women in the United States. These deaths are most often caused by the spread of breast cancer to other sites of the body, a process that involves genes normally reserved for wound healing. Research on the wound response genes in breast cancer will help to improve the risk assessment of breast cancer patients and identify targets for cancer therapy.