Wound Response Genes in Cancer Progression

癌症进展中的伤口反应基因

基本信息

批准号：
7422379
负责人：
Howard Y Chang
金额：
$ 29.74万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7422379
关键词：
Biochemical Blood Vessels Breast Breast Cancer Model Cancer Etiology Cancer Patient Catalytic Domain Cell Proliferation Cell division Cells Cessation of life Collaborations Complex Development Epithelial Epithelial Cells Extracellular Matrix FBXW7 gene Gene Expression Profile Gene Mutation Gene Targeting Genes Genetic Genetic screening method Genomic Instability Genomics Growth Half-Life Healed Human Human body Hyperplasia In Vitro Invasive Lesion Life Cycle Stages MYC Box MYC Family Protein Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mediating Modeling Molecular Mus Natural regeneration Neoplasm Metastasis Nuclear Export Oncogene Proteins Oncogenes Oncogenic Pathologic Pathway interactions Pharmaceutical Preparations Physiological Post-Translational Protein Processing Process Protein Overexpression Proteins Recruitment Activity Regulation Research Research Personnel Risk Risk Assessment Risk Factors Role SKP Cullin F-Box Protein Ligases SKP2 gene Signal Transduction Site Skp2 Proteins Specificity Staging Stem cells Therapeutic Intervention Tissues Ubiquitin Ubiquitination United States Woman Wound Healing angiogenesis base c-myc Genes cancer cell cancer therapy cyclin-dependent kinase inhibitor 1B healing improved in vivo isopeptidase malignant breast neoplasm migration novel p27 Cell Cycle Protein p27 Enzyme Inhibitor programs protein protein interaction repaired response self-renewal small molecule therapeutic target transcription factor tumor tumor progression ubiquitin ligase wound

项目摘要

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.

描述（由申请人提供）：人体具有巨大的愈合能力，但是细胞生长，再生组织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，尤其是乳腺癌中，肿瘤在伤口反应模型中正常观察到的基因的能力是随后转移的强大而准确的预测指标。我们发现人乳腺肿瘤中的特定遗传突变驱动伤口反应签名的表达。两个基因CSN5和MYC的扩增会激活伤口反应的特征，并导致细胞分裂和侵袭增加。 CSN5激活泛素对MYC癌蛋白的翻译后修饰，从而激活MYC的活性。但是，尚不清楚伤口特征激活的分子机制及其在癌症进展中的致病机制尚不清楚。因此，我们建议研究CSN5和MYC如何在两个目标中激活伤口特征和乳腺癌转移。首先，我们将确定CSN5及其相关COP9复合物的哪些酶活性对于CSN5激活MYC并增强体内肿瘤进展至关重要。 CSN5的异肽酶活性高度适应小分子药物的抑制作用，因此可以在乳腺癌中提出一个有吸引力的治疗靶标。其次，我们将确定CSN5如何在两个拮抗泛素连接酶途径之间选择以激活MYC。这些研究将阐明与乳腺癌进展有关的新途径，并确定特定的治疗干预靶标。乳腺癌是美国女性癌症死亡的第二大最常见原因。这些死亡通常是由乳腺癌扩散到人体其他部位的原因，该过程涉及通常用于伤口愈合的基因。乳腺癌中伤口反应基因的研究将有助于改善乳腺癌患者的风险评估，并确定癌症治疗的靶标。