Cannabinoids Control Breast Cancer Progression Through Id-1

描述(由申请人提供)：癌症进展的路径由生长/侵袭和分化的调节机制的变化决定。ID-1蛋白(一种碱性螺旋-环-螺旋转录因子的抑制因子)的表达在20多种类型的癌症中表达异常，并被认为是肿瘤发生和/或转移的关键决定因素，在广泛的组织中，特别是在乳腺癌中。我们对ID-1基因在正常乳腺细胞、癌变乳腺细胞、小鼠乳腺组织和人乳腺癌组织中的表达进行了研究，结果表明ID-1基因的表达与乳腺癌细胞的增殖、迁移和侵袭表型有关。因此，降低ID-1的表达可以为侵袭性乳腺癌的治疗提供一种合理的治疗策略。我们最近发现，CBD是一种从大麻中提取的非精神活性大麻素化合物，可能是第一个无毒的外源性药物，可以下调ID-1的表达。这种下调，以及相应的对人乳腺癌细胞增殖和侵袭的抑制，可能为该化合物的抗转移活性提供了一个潜在的机制。这项建议的目的是确定1)新的CBD类似物在多大程度上通过下调ID-1来降低小鼠乳腺癌细胞的增殖、侵袭和转移进展，以及2)大麻类化合物抑制ID-1表达的机制。拟议的实验有可能导致开发用于治疗乳腺癌转移的新化合物。此外，从概述的实验中获得的信息将极大地拓宽我们对ID-1和大麻素生物学的知识，因为它与癌症进展有关。了解这些分子事件也可能导致未来开发新的、有效的和无毒的乳腺癌治疗方法。 与公共卫生相关：我们假设，大麻类化合物是一种耐受性良好的化合物，已经用于临床试验，目的与其抗癌活性无关，它将通过下调ID-1表达和相应的乳腺癌细胞侵袭和转移的能力而对乳腺癌患者有利。利用可以模拟ID-1蛋白在人类肿瘤进展过程中作用的小鼠模型，我们希望开发新的策略来专门针对其表达用于治疗目的。这项研究可能会在治疗侵袭性乳腺癌方面带来新的研究领域，这种乳腺癌扩散到身体的其他部位，使用新的大麻类化合物，如大麻二酚的类似物。

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.