Aberrant Retinoid Signaling in Breast Cancer

乳腺癌中的异常视黄醇信号传导

基本信息

批准号：
7741226
负责人：
Eduardo F Farias
金额：
$ 28.87万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-04-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7741226
关键词：
Address Advocate Agonist All-Trans-Retinol Am 580 Automobile Driving BRCA1 gene Binding Biological Models Breast Carcinogenicity Tests Cell Differentiation process Cell model Cells Characteristics Chemopreventive Agent Clinical Trials Conflict (Psychology)Data Development Disease Dominant-Negative Mutation Duct (organ) structure Epidermal Growth Factor Receptor Epithelial Cells Epithelium Event Funding Future Genes Genetic Genetically Engineered Mouse Growth In Vitro Knockout Mice Knowledge Laboratories Lead Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Modeling Molecular Mouse Mammary Tumor Virus Mus Mutant Strains Mice Nature Oncogenes Oncogenic Pathway interactions Patients Pharmaceutical Preparations Phase Predisposition Protein Isoforms Protocols documentation Puberty Receptor Inhibition Regulation Reporter Retinoic Acid Receptor Retinoids Role Signal Transduction Sum Testing Transgenic Mice Transgenic Model Transgenic Organisms Work base cancer prevention carcinogenesis cell growth cohort gene function improved in vitro activity in vivo interest malignant breast neoplasm mammary epithelium mouse model novel null mutation overexpression paracrine prevent receptor function tumor tumorigenesis

项目摘要

We are working toward elucidating the role of retinoic acid receptors (RARs) in mammary development and carcinogenesis and understanding the role of genes that function upstream of RARs to regulate their activity. Using genetically engineered mouse models, we demonstrated that RARs function as rheostats that up or downregulate mammary cancer predisposition in an oncogene-dependent manner and obtained preliminary evidence that RARs can also function as on-off switches that initiate mammary carcinogenesis. Further, we demonstrated that the cellular retinol-binding proteinl (CRBP1) is a positive upstream regulator of RAR activity and that CRBP1/RAR promote cell differentiation and suppress cell growth by inhibiting the PI3K/Akt survival pathway through a novel mechanism. RARs also regulate mammary duct development during puberty, a key developmental phase regulated by genes such as EGFR, BRCA1, etc. Our continuation aim 1 will elucidate the cellular basis of this developmental effect (cell autonomous vs. paracrine vs. systemic); test the notion that retinoid (Am580) treatment will prevent/slow tumor development in MMTV-Wnt1 mice but accelerate tumor development in MMTV-Neu mice; and identify the mechanism through which RAR inhibits Wnt signaling. Aim 2 will test the hypothesis that gobal RAR inhibition is sufficient to initiate mammary carcinogenesis using transgenic models in which a dominant negative RAR is expressed in the mammary epithelium. Aim 3 will further define the mechanim whereby CRBP1, acting through RAR, inhibits PI3K activity and will test whether CRBP1 is a positive upstream regulator of RAR activity in vivo. The class of drugs referred to as retinoids are promising agents in cancer prevention and treatment but so far clinical trials have not identified specific cancer cohorts in which retinoid treatment improves overall survival. Our studies demonstrate that the effect of retinoic acid receptors (the target of retinoids) is dependent on the nature of the oncogenic pathway behind the disease and that in some cases retinoid treatment stands to be beneficial but in others it might be counterproductive. This has direct implications to future retinoid clinical trials in that it advocates that participating patients be carefully stratified based on the molecular characteristics of their cancer.

我们正在努力阐明视黄酸受体（RARS）在乳腺发育中的作用癌变和理解在上游的基因在调节活性上的作用。使用基因工程的鼠标模型，我们证明了RAR的作用是升级或以癌基因依赖性方式下调乳腺癌易感性，并获得了初步证据表明RAR还可以充当启动乳腺癌发生的开关开关。此外，我们证明细胞视黄醇结合蛋白（CRBP1）是RAR的正上游调节剂活性和CRBP1/RAR通过抑制PI3K/AKT促进细胞分化并抑制细胞生长通过一种新型机制的生存途径。 RARS还调节乳腺导管的发育青春期，由EGFR，BRCA1等基因调节的关键发展阶段。我们的延续目标1 将阐明这种发育效果的细胞基础（细胞自主与旁分泌与全身性）；测试类视黄（AM580）治疗将预防/缓慢的MMTV-WNT1小鼠肿瘤发展的观念，但 MMTV-NEU小鼠的加速肿瘤发展；并确定RAR抑制的机制 wnt信号传导。 AIM 2将检验以下假设：Gobal RAR抑制足以启动乳腺使用转基因模型的致癌作用，其中乳腺中显性负RAR的显性负RAR表示上皮。 AIM 3将进一步定义CRBP1通过RAR抑制PI3K的机制活性并将测试CRBP1是否是体内RAR活性的正面调节剂。被称为类维生素的药物类别是预防癌症和治疗方面的有前途的药物，但远处的临床试验尚未鉴定特定的癌症同类群，其中类视黄素治疗可以改善总体生存。我们的研究表明，视黄酸受体的影响（视视网膜类动物的靶标）为取决于疾病背后的致癌途径的性质，在某些情况下是类似性的治疗是有益的，但在其他方面可能会适得其反。这与未来的类维生素性临床试验，它提倡根据其癌症的分子特征。