Retinoic acid, CRABP, and cancer

描述（由申请人提供）：维甲酸（RA）在包括乳腺癌在内的许多癌症中具有化疗和化学预防活性。然而，类风湿关节炎的治疗由于该药物在药理学剂量下的明显毒性和肿瘤中类风湿关节炎耐药性的发展而受到混淆。RA的生物活性是由核激素受体视黄酸和类视黄酸X受体（RARs和RXRs）介导的。此外，RA在细胞内结合两种细胞内蛋白，细胞RA结合蛋白I和II （CRABP-I和CRABP-II）。我们之前发现CRABP-II（而不是CRABP-I）促进RA传递到被其激活的受体，即RAR。我们进一步发现，CRABP-II的这种活性增强了RAR的转录活性，表明该结合蛋白的存在可能使细胞对RA的生物活性敏感。我们最近的数据确实表明，在两种乳腺癌小鼠模型中，CRABP-II的表达增强了培养的乳腺癌细胞对ra诱导的生长抑制的反应性，并抑制了肿瘤的发展。因此，CRABP-II可能是治疗和预防某些癌症的新靶点。为了更好地了解RA和CRABP-II在乳腺癌中的活性机制，本应用程序有以下具体目的：(1)在MCF-7乳腺癌细胞中鉴定受RA和CRABP-II调控的靶基因。Affymetrix表达阵列将用于比较表达不同水平CRABP-II的MCF-7细胞的基因表达谱，在没有或接受RA治疗的情况下。(2)研究CRABP-II和RA对转基因乳腺癌小鼠模型肿瘤生长的影响。将使用小鼠模型MMTV-neu/ erbb - b2，其中乳腺肿瘤自发产生并在免疫监视下进展。将生成两种小鼠模型：在乳腺组织中中断CRABP-II表达的mmtv - new小鼠和过表达CRABP-II的mmtv - new小鼠。在表达不同水平CRABP-II的小鼠中发展的肿瘤特征将使我们能够评估该蛋白抑制肿瘤发生和使乳腺肿瘤对ra诱导的体内生长抑制敏感的能力。此外，Affymetrix阵列将用于分析参与CRABP-II表达和RA给药对mmtv - new小鼠肿瘤生长影响的基因。

DESCRIPTION (provided by applicant): Retinoic acid (RA) exhibits chemotherapeutic and chemopreventive activities in a number of cancers, including breast cancer. RA therapy is however confounded by a marked toxicity of this agent at pharmacological doses and by development of RA-resistance in tumors. The biological activities of RA are mediated by the nuclear hormone receptors retinoic acid- and retinoid X- receptors (RARs and RXRs). In addition, RA binds in cells to two intracellular proteins, cellular RA binding proteins I and II (CRABP-I and CRABP-II). We previously found that CRABP-II (but not CRABP-I) facilitates the delivery of RA to the receptor that is activated by it, namely RAR. We found further that this activity of CRABP-II enhances the transcriptional activity of RAR, suggesting that the presence of the binding protein could sensitize cells to the biological activities of RA. Our recent data indeed indicate that CRABP-II expression enhances the responsiveness of cultured mammary carcinoma cells to RA-induced growth inhibition, and suppresses tumor development in two mouse models of breast cancer. Hence, CRABP-II may comprise a novel target for therapy and prevention of some cancers. To better understand the mechanisms underlying the activities of RA and CRABP-II in mammary carcinomas, this application has the following specific aims: (1) To identify target genes that are regulated by RA and CRABP-II in MCF-7 mammary carcinoma cells. Affymetrix expression arrays will be utilized to compare gene expression profiles of MCF-7 cells that express different levels of CRABP-II, in the absence of or upon treatment with RA. (2) To study the effects of CRABP-II and RA on tumor growth in transgenic breast cancer mouse models. The mouse model MMTV-neu/Erb-B2, in which breast tumors arise spontaneously and progress under immune surveillance, will be used. Two mouse models will be generated: MMTV-neu mice with disrupted expression of CRABP-II, and MMTV-neu mice that over-express CRABP-II in mammary tissue. Characterization of tumors that develop in mice expressing different levels of CRABP-II will allow us to assess the ability of the protein to inhibit tumorigenesis and to sensitize breast tumors to RA-induced growth inhibition in vivo. In addition, Affymetrix arrays will be used to analyze genes that are involved in the effects of CRABP-II expression and RA administration on tumor growth in MMTV-neu mice.