Wound Response Genes in Cancer Progression

描述（由申请人提供）：人体具有巨大的愈合能力，但细胞生长、组织再生和招募新血管的能力也可能在癌症进展过程中被滥用。在许多常见的癌症中，尤其是乳腺癌，肿瘤表达在伤口反应模型中常见的基因的能力是随后转移的一个强大而准确的预测指标。我们发现人类乳腺肿瘤中特定的基因突变驱动了伤口反应特征的表达。CSN5和MYC两个基因的扩增激活了伤口反应信号，导致细胞分裂和侵袭增加。CSN5通过泛素激活MYC癌蛋白的翻译后修饰，从而激活MYC的活性。然而，伤口特征激活的分子机制及其在体内肿瘤进展中的致病机制尚不清楚。因此，我们提出从两个方面研究CSN5和MYC如何激活伤口特征和乳腺癌转移。首先，我们将确定CSN5及其相关的COP9复合物的哪些酶活性对CSN5激活MYC和促进体内肿瘤进展是重要的。CSN5的异肽酶活性极易受到小分子药物的抑制，因此可能成为乳腺癌的一个有吸引力的治疗靶点。其次，我们将确定CSN5如何在两种拮抗泛素连接酶途径中选择激活MYC。这些研究将阐明与乳腺癌进展有关的新途径，并确定治疗干预的具体目标。乳腺癌是美国女性癌症死亡的第二大常见原因。这些死亡通常是由乳腺癌扩散到身体其他部位引起的，这一过程涉及到通常为伤口愈合保留的基因。研究乳腺癌的创伤反应基因有助于提高乳腺癌患者的风险评估和确定癌症治疗的靶点。

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.