BRCA Genes in Breast Cancer Chemoprevention

简介(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]对激素依赖型肿瘤具有化学预防活性，包括乳腺癌、宫颈癌和子宫内膜癌。其抗肿瘤活性可能是由于激素依赖和激素非依赖性作用所致。乳腺癌易感基因BRCA1和BRCA2的突变都会显著增加几种激素敏感型癌症(例如乳腺癌和前列腺癌)的风险。初步研究。我们已发表的和初步的研究表明，在人类乳腺癌、宫颈癌和前列腺癌细胞系中，DC的一些激素依赖和激素非依赖性的作用是通过上调BRCA1和BRCA2的表达来实现的。使用DNA微阵列进行的基因表达谱分析表明，DM(ISC的主要活性代谢物)诱导的基因表达模式与BRCA1之间存在重叠。假设。我们推测，I3C的化学预防部分是由于BRCA1(可能还有BRCA2)介导的活动：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(GADS)和GSTs。I3C也可能诱导这些和其他独立于BRCA1的肿瘤抑制途径；BRCA1/2可能与这些其他I3C途径协同作用，抑制肿瘤的发生。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；我们将利用我们已经开发的每个BRCA基因的小干扰RNA，评估内源性BRCA基因在I3C在人乳腺上皮细胞中对雌激素依赖和雌激素非依赖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变化中的作用。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，这些模型通过饮食补充I3C来预防乳腺癌。其中一个模型将以针对乳房的Brcal突变为特色。意义重大。这些研究将确定BRCA基因是吲哚-3-甲醇的分子靶点，吲哚-3-甲醇有助于其预防乳腺癌的能力。这些研究的成功结果将建议在散发性和遗传性乳腺癌的化学预防中使用I3C。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侵袭。

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.