Cannabinoids Control Breast Cancer Progression Through Id-1

大麻素通过 Id-1 控制乳腺癌进展

基本信息

批准号：
8300959
负责人：
Sean D McAllister
金额：
$ 33.96万
依托单位：
CALIFORNIA PACIFIC MED CTR RES INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-28 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300959
关键词：
Animals Antisense Technology Area BHLH Protein Basic Science Biological Assay Biology Biopsy Body part Breast Breast Cancer Cell Cancer Patient Cancerous Cannabidiol Cannabinoids Cannabis Cell Cycle Cell Cycle Arrest Cell Differentiation process Cell Proliferation Cell Separation Cells Characteristics Clinical Trials Data Development Down-Regulation Drug Design Epithelial Epithelial Cells Event Foundations Future Gene Expression Generations Growth Helix-Turn-Helix Motifs Human Immunohistochemistry In Situ Hybridization In Vitro Investigation Knowledge Lead Lung MDA MB 231 Mammary gland Matrix Metalloproteinases Mediating Messenger RNA Mitogen-Activated Protein Kinases Molecular Mus Neoplasm Metastasis Oxidases Pathway interactions Patients Peptide Hydrolases Phase Phenotype Primary Neoplasm Production Protein Kinase Inhibitors Proteins Reporting Research Role Series Signal Transduction Small Interfering RNA Structure Testing Therapeutic Therapeutic Agents Tissues Up-Regulation analog anticancer activity base cancer cell cancer type carcinogenesis in vitro activity in vivo inhibitor/antagonist malignant breast neoplasm mouse model novel novel strategies promoter protein kinase inhibitor public health relevance research study transcription factor treatment strategy tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The path of cancer progression is determined by alterations in the regulatory mechanisms of growth/invasion and differentiation. The expression of Id-1 protein (an inhibitor of basic helix-loop-helix transcription factors) has been reported to be dysregulated in over twenty types of cancer, and suggested as a key determinant of tumorigenesis and/or metastasis in a wide range of tissues, particularly in the breast. Our studies on Id-1 expression in normal and cancerous breast cells, in mouse mammary glands as well as in human breast cancer biopsies, demonstrated that Id-1 gene expression was associated with a proliferative, migratory and invasive phenotype. Reducing Id-1 expression could therefore provide a rational therapeutic strategy for the treatment of aggressive breast cancer. We recently showed that CBD, a non-psychoactive cannabinoid compound derived from cannabis, could represent the first non-toxic exogenous agent that can down-regulate Id-1 expression. This down-regulation, and the corresponding inhibition of human breast cancer cell proliferation and invasiveness, could provide a potential mechanism for the anti-metastatic activity of the compound. The aims of this proposal are to determine 1) the extent to which novel CBD analogs reduce breast cancer cell proliferation, invasion and metastatic progression in mice through Id-1 down-regulation, and 2) the mechanisms behind the inhibition of Id-1 expression by cannabinoid compounds. The proposed experiments have the potential to lead to the development of novel compounds for the treatment of breast cancer metastasis. Additionally, the information gained from the outlined experiments will greatly broaden our knowledge of both Id-1 and cannabinoid biology as it pertains to cancer progression. Understanding these molecular events may also lead to the future development of novel, efficacious and non-toxic treatments for breast cancer patients. PUBLIC HEALTH RELEVANCE: We hypothesize that cannabinoids, well-tolerated compounds that are already being used in clinical trials for purposes unrelated to their anticancer activity, will be of benefit for patients with breast cancers through their ability to down-regulate Id-1 expression and corresponding breast cancer cell invasion and metastasis. Using mouse models that can mimic the role of Id-1 protein during tumor progression in humans, we expect to develop novel strategies to specifically target its expression for therapeutic purposes. This research could lead to new areas of investigation in the treatment of aggressive forms of breast cancer, which spread to other parts of the body, with novel cannabinoid compounds such as analogs of cannabidiol.

描述（由申请人提供）：癌症进展的路径取决于生长/入侵和分化的调节机制的改变。据报道，ID-1蛋白的表达（基本螺旋 - 环螺旋转录因子的抑制剂）在二十多种癌症中失调，并建议是肿瘤发生和/或转移的关键决定因素，尤其是在乳房中，尤其是在乳房中。我们在正常和癌细胞中ID-1表达的研究，小鼠乳腺以及人类乳腺癌活检中的研究表明，ID-1基因表达与增殖，迁移和侵入性表型有关。因此，减少ID-1表达可以为治疗侵袭性乳腺癌提供合理的治疗策略。我们最近表明，CBD是一种源自大麻的非精神活性大麻素化合物，可以代表第一种可以下调ID-1表达的无毒外源性剂。这种下调以及对人类乳腺癌细胞增殖和侵袭性的相应抑制，可以为化合物的抗转移活性提供潜在的机制。该提案的目的是确定1）新型CBD类似物在多大程度上通过ID-1下调减少小鼠中乳腺癌细胞的增殖，侵袭和转移性进展，2）大麻素化合物抑制ID-1表达的机制。提出的实验有可能导致开发用于治疗乳腺癌转移的新型化合物。此外，从概述的实验中获得的信息将大大扩展我们对ID-1和大麻素生物学的了解，因为它与癌症的进展有关。了解这些分子事件也可能导致对乳腺癌患者的新型，有效和无毒治疗的未来发展。公共卫生相关性：我们假设大麻素，耐受耐受性的化合物已经在临床试验中使用，目的是与其抗癌活性无关的目的，对于乳腺癌的患者而言，将通过下调ID-1表达和相应的乳腺癌细胞入侵和转移和转移而受益。使用可以模仿ID-1蛋白在人类肿瘤进展中的作用的小鼠模型，我们希望开发出新颖的策略，以专门针对其用于治疗目的的表达。这项研究可能会导致新的研究领域，用于治疗侵略性形式的乳腺癌，这些乳腺癌扩散到人体其他部位，并具有新型的大麻素化合物，例如大麻二酚的类似物。