BRCA Genes in Breast Cancer Chemoprevention

BRCA 基因在乳腺癌化学预防中的作用

• 批准号: 7024493
• 负责人: Eliot M. Rosen
• 金额: $ 29.93万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7024493
• 关键词: RNA interference; brca gene; breast neoplasms; cell growth regulation; chemoprevention; dietary supplements; estrogens; gene environment interaction; gene expression; gene induction /repression; gene mutation; genetic transcription; genetically modified animals; hormone regulation /control mechanism; indoles; laboratory mouse; mammary epithelium; microarray technology; neoplasm /cancer nutrition therapy; nonhuman therapy evaluation; nutrition aspect of cancer; nutrition related tag

DESCRIPTION (provided by applicant): Background. Clinical-epidemiological and animal model studies suggest that indole-3-carbinol [I3C, a phytochemical from cruciferous vegetables] has chemopreventive activity for hormone-dependent tumor types, including breast, cervical, and endometrial cancers. Its anti-tumor activity is probably due to both hormone-dependent and hormone independent actions. Mutations of the breast cancer susceptibility genes BRCA1 and BRCA2 each confer a significantly increased risk of several hormonally-responsive cancer types (e.g., breast and prostate cancers). Preliminary studies. Our published and preliminary studies suggest that some of the hormone-dependent and hormone-independent actions of DC in human breast, cervical cancer, and prostate cell lines are mediated through the up-regulation of BRCA1 and BRCA2 expression. Gene expression profiling using DNA microarrays suggest an overlap between the gene expression patterns induced by DM (the major active metabolite of ISC) vs BRCA1. Hypothesis. We postulate that chemoprevention by I3C is due, in part, to BRCA1 (and probably BRCA2) mediated activities: e.g., inhibition of E2-stimulated cell growth and up-regulation of growth arrest and DNA damage-responsive genes (GADDs) and GSTs. I3C may also induce these and other tumor suppressor pathways independently of BRCA1; and BRCA1/2 may function synergistically with these other I3C pathways to suppress tumorigenesis. Objectives. To test these hypotheses, we will carry out three specific aims. In SA1, we will investigate the mechanism by which I3C induces BRCA1 and BRCA2; and we will assess the contribution of the endogenous BRCA genes to the estrogen-dependent and estrogen-independent molecular and cellular actions of I3C in human mammary epithelial cells, using small interfering RNAs to each BRCA gene that we have already developed. In SA2, we will assess the roles of the BRCA genes in the spectrum of DBVI-induced transcriptional alterations in mammary epithelial cells. And in SA3, we will validate some of these in vitro observations using two in vivo experimental models for prevention of mammary cancer by dietary supplementation with I3C. One model will feature a mammary-targeted mutation of Brcal. Significance. These studies will establish that the BRCA genes are molecular targets for indole-3-carbinol that contribute to its ability to prevent breast cancer. A successful outcome of these studies would suggest the use of I3C in chemoprevention of sporadic and hereditary breast cancers. The latter may be particularly useful, since recent studies suggest that Tamoxifen may not protect women with BRCA1 mutations from developing breast cancer.

描述（由申请人提供）：背景。临床流行病学和动物模型研究表明，吲哚-3-甲醇[I3C，一种十字花科蔬菜的植物化学]具有化学预防活性，可用于激素依赖性肿瘤类型，包括乳腺癌，颈椎，子宫内膜和子宫内膜癌。它的抗肿瘤活性可能是由于激素依赖性和激素独立作用引起的。乳腺癌敏感性基因BRCA1和BRCA2的突变各自赋予了几种激素反应性癌症类型（例如乳腺癌和前列腺癌）的风险显着增加。初步研究。我们发表的初步研究表明，DC在人乳腺，宫颈癌和前列腺细胞系中的某些激素依赖性和激素独立的作用是通过BRCA1和BRCA2表达的上调来介导的。使用DNA微阵列进行基因表达分析表明，DM（ISC的主要活性代谢产物）与BRCA1诱导的基因表达模式之间存在重叠。假设。我们假设I3C的化学预防部分归因于BRCA1（以及可能是BRCA2）介导的活性：例如，抑制E2刺激的细胞生长以及对生长停滞的上调以及DNA损伤反应性基因（GADDS）和GSTS的上调。 I3C也可能独立于BRCA1诱导这些和其他肿瘤抑制途径。 BRCA1/2可能与这些其他I3C途径协同作用以抑制肿瘤发生。目标。为了检验这些假设，我们将执行三个具体目标。在SA1中，我们将研究I3C诱导BRCA1和BRCA2的机制；我们将使用小的干扰RNA对我们已经开发的每个BRCA基因，评估内源性BRCA基因对I3C在人类乳腺上皮细胞中I3C的雌激素依赖性和雌激素独立的分子和细胞作用的贡献。在SA2中，我们将评估BRCA基因在DBVI诱导的乳腺上皮细胞转录改变谱中的作用。在SA3中，我们将使用两个体内实验模型来验证其中一些体外观察结果，以预防饮食中的I3C来预防乳腺癌。一种模型将具有BRCAL的乳腺靶向突变。意义。这些研究将确定BRCA基因是吲哚-3-甲醇的分子靶标，有助于其预防乳腺癌。这些研究的成功结果表明，使用I3C在零星和遗传性乳腺癌的化学预防中使用。后者可能特别有用，因为最近的研究表明他莫昔芬可能无法保护BRCA1突变的女性免受乳腺癌的发展。