Cannabinoids Control Breast Cancer Progression Through Id-1

描述（由申请人提供）：癌症进展的途径是由生长/侵袭和分化调节机制的改变决定的。Id-1蛋白（一种碱性螺旋-环-螺旋转录因子的抑制剂）的表达在超过20种类型的癌症中失调，并被认为是广泛组织中肿瘤发生和/或转移的关键决定因素，特别是在乳腺中。我们对正常和癌乳腺细胞、小鼠乳腺以及人乳腺癌活检中Id-1表达的研究表明，Id-1基因表达与增殖、迁移和侵袭性表型相关。因此，减少Id-1表达可能为治疗侵袭性乳腺癌提供一种合理的治疗策略。我们最近发现，从大麻中提取的一种非精神活性大麻素化合物CBD可能是第一个可以下调Id-1表达的无毒外源性药物。这种下调，以及相应的对人乳腺癌细胞增殖和侵袭性的抑制，可能为该化合物的抗转移活性提供了潜在的机制。本研究的目的是确定1)新型CBD类似物通过下调Id-1在小鼠中抑制乳腺癌细胞增殖、侵袭和转移进展的程度，以及2)大麻素化合物抑制Id-1表达的机制。所提出的实验有可能导致开发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大大拓宽我们对Id-1和大麻素生物学的认识，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、无毒的乳腺癌治疗方法。

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.