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，indole-3-carbinol [I3C，一种来自十字花科蔬菜的植物化学物质] 对激素依赖性肿瘤类型（包括乳腺癌、宫颈癌和子宫内膜癌）具有化学预防活性。其抗肿瘤活性可能是由于激素依赖性和激素非依赖性作用所致。乳腺癌易感基因 BRCA1 和 BRCA2 的突变都会显着增加几种激素反应性癌症类型（例如乳腺癌和前列腺癌）的风险。初步研究。我们已发表的初步研究表明，DC 在人类乳腺癌、宫颈癌和前列腺细胞系中的一些激素依赖性和激素非依赖性作用是通过 BRCA1 和 BRCA2 表达上调介导的。使用 DNA 微阵列进行的基因表达谱表明 DM（ISC 的主要活性代谢物）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（可能还有 BRCA2）介导的活性：例如，抑制 E2 刺激的细胞生长以及上调生长停滞和 DNA 损伤反应基因 (GADD) 和 GST。 I3C 也可能独立于 BRCA1 诱导这些和其他肿瘤抑制途径； BRCA1/2 可能与其他 I3C 通路发挥协同作用，抑制肿瘤发生。目标。为了检验这些假设，我们将实现三个具体目标。在SA1中，我们将研究I3C诱导BRCA1和BRCA2的机制；我们将使用我们已经开发的每个 BRCA 基因的小干扰 RNA，评估内源性 BRCA 基因对人类乳腺上皮细胞中 I3C 的雌激素依赖性和雌激素非依赖性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验证其中一些体外观察结果，通过饮食补充 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的能力。这些研究的成功结果表明 I3C 可用于散发性和遗传性乳腺癌的化学预防。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携带 BRCA1 突变的女性免患乳腺癌。