BRCA Genes in Breast Cancer Chemoprevention

BRCA 基因在乳腺癌化学预防中的作用

• 批准号: 7416594
• 负责人: Eliot M. Rosen
• 金额: $ 28.61万
• 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/7416594
• 关键词: Animal Model; Antioxidants; BRCA1 Mutation; BRCA1 gene; BRCA2 gene; Biological Assay; Breast; Breast Cancer Prevention; Cancer-Predisposing Gene; Carcinogen Metabolism; Carcinogens; Categories; Cell Line; Cells; Cervical; Chemoprevention; Chemopreventive Agent; Clinical; DNA Damage; DNA Microarray Chip; DNA Microarray format; Data; Dietary Supplementation; Endometrial Carcinoma; Epithelial Cells; Estrogens; Exons; Experimental Animal Model; Experimental Models; Figs - dietary; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Glutathione; Goals; Growth; Hereditary Breast Carcinoma; Hormones; Human; In Vitro; Indole-3-Carbinol; Malignant neoplasm of cervix uteri; Malignant neoplasm of prostate; Mammary Tumorigenesis; Mammary gland; Mediating; Messenger RNA; Metabolism; Modeling; Molecular; Molecular Target; Mus; Mutation; Outcome Study; Pathway interactions; Pattern; Phytochemical; Prevention; Prostate; Proteins; Publishing; Risk; Role; Small Interfering RNA; Tamoxifen; Testing; Toxic effect; Transcriptional Activation; Tumor Suppressor Proteins; Up-Regulation; Woman; cancer type; cell growth; cruciferous vegetable; falls; in vivo; malignant breast neoplasm; mouse model; prevent; repaired; response; sulfotransferase; transcription factor; tumor; tumorigenesis

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）具有化学预防作用。其抗肿瘤活性可能与激素依赖性和激素非依赖性双重作用有关。乳腺癌易感基因BRCA1和BRCA2的突变都会显著增加患几种激素反应性癌症类型（如乳腺癌和前列腺癌）的风险。初步研究。我们发表的和初步的研究表明，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上调BRCA1和BRCA2表达来介导的。使用DNA微阵列进行基因表达谱分析表明，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的化学预防部分是由于BRCA1（也可能是BRCA2）介导的活性：例如，抑制e2刺激的细胞生长，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通路；BRCA1/2可能与其他I3C通路协同作用，抑制肿瘤发生。目标。为了验证这些假设，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；我们将评估内源性BRCA基因对人类乳腺上皮细胞中I3C依赖雌激素和不依赖雌激素的分子和细胞作用的贡献，使用我们已经开发的每个BRCA基因的小干扰rna。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，我们将通过两种体内实验模型验证一些体外观察结果，通过膳食补充I3C来预防乳腺癌。其中一个模型将以Brcal的乳腺靶向突变为特征。的意义。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将提示I3C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，他莫昔芬可能不能保护携带BRCA1突变的女性不患乳腺癌。