Isothiocyanate-Mediated Breast Cancer Prevention

描述（由申请人提供）：本研究的主要目的是测试膳食萝卜硫素（SFN）预防“自发”或癌基因诱导的乳腺癌的能力，从而为SFN介导的乳腺癌抑制的新机制研究建立一个可处理的系统。SFN是一种膳食异硫氰酸盐，在食用十字花科蔬菜（如花椰菜）时产生一种前体化合物（葡萄糖苷），而花椰菜是SFN前体的特别丰富来源。与一些观察性研究中发现的十字花科蔬菜摄入量与乳腺癌风险呈负相关一致，SFN在实验性乳腺癌模型中具有强大的抗癌活性。具体来说，SFN可以防止致癌物治疗引起的啮齿动物乳腺瘤变，这很可能是II期酶诱导和致癌物失活加速的结果。然而，最近发现SFN通过抑制组蛋白去乙酰化酶（HDAC）活性作为一种表观遗传调节剂。引人注目的是，SFN已被证明在小鼠和人体内和体外都能改变组蛋白乙酰化状态。在这里，我们建议使用不依赖于致癌物质或“自发”的乳腺癌模型来研究SFN，在该模型中，雌激素受体（ER）阴性的乳腺肿瘤是由癌基因过表达驱动的。这种广泛使用的小鼠模型应该为最终评估sfn介导的HDAC抑制的重要性提供一个有用的实验系统。SFN将以西兰花芽的形式传递，这是SFN前体的特别丰富的来源。这提供了最大的翻译相关性，因为正在进行的nci资助的试验正在测试西兰花芽SFN在乳腺和前列腺上皮内瘤变患者中的作用。本文提出的研究目标有两个方面。首先，我们将测试日粮中添加SFN对肿瘤形成、增殖、生长速度和转移的影响。其次，我们将研究sfn介导的小鼠乳腺组织中生物终点的调节，使用正常和癌前乳腺组织和乳腺癌。检测将包括：HDAC活性和组蛋白乙酰化状态、II期酶表达、增殖和凋亡。此外，我们将比较对照组和sfn治疗小鼠肿瘤中的ER表达。这些初步研究将为未来r01规模的研究奠定基础，以建立观察到的变化与SFN介导的肿瘤保护之间的因果关系，并研究SFN在表观遗传学上恢复ER阴性癌症对内分泌治疗的敏感性方面的效用。我们预计从这些研究中获得的数据将对临床研究中生物标志物的选择非常重要

DESCRIPTION (provided by applicant): The main goals of this research are to test the ability of dietary sulforaphane (SFN) to prevent "spontaneous", or oncogene-induced, breast cancer, and thereby to establish a tractable system for novel mechanistic studies of SFN-mediated breast cancer suppression. SFN is a dietary isothiocyanate derived from a precursor compound (glucoraphanin) during consumption of cruciferous vegetables such as broccoli, a particularly rich source of the SFN precursor. Consistent with the inverse relationship between cruciferous vegetable intake and breast cancer risk identified in some observational studies, SFN has potent anticancer activity in experimental breast cancer models. Specifically, SFN protects against rodent breast neoplasia induced by carcinogen treatment, most likely as a consequence of Phase II enzyme induction and resultant acceleration of carcinogen deactivation. Recently however, a novel activity has been identified for SFN as an epigenetic modulator through inhibition of histone deacetylase (HDAC) activity. Strikingly, SFN has been shown to alter histone acetylation status both in vitro and in vivo in mice and humans. Here we propose to study SFN using a carcinogen-independent or "spontaneous" breast cancer model in which estrogen receptor (ER) -negative breast neoplasia is driven by oncogene overexpression. This widely used mouse model should provide a useful experimental system in which to ultimately evaluate the importance of SFN-mediated HDAC inhibition. SFN will be delivered in the form of broccoli sprouts, an exceptionally rich source of the SFN precursor. This provides maximal translational relevance since ongoing NCI-funded trials are testing broccoli sprout SFN in patients with breast and prostate intraepithelial neoplasia. The goals of the research proposed herein are two- fold. Firstly, we will test the effect of dietary SFN on tumor formation, multiplicty, growth rate and metastasis. Secondly, we will examine SFN-mediated modulation of biological endpoints in mouse mammary tissues, using normal and precancerous breast tissues and breast carcinomas. Assays will include: HDAC activity and histone acetylation status, Phase II enzyme expression, proliferation and apoptosis. Additionally, we will compare ER expression in tumors from control and SFN-treated mice. These pilot studies will lay the foundation for future R01-scale investigations to establish causal links between observed changes and SFN- mediated tumor protection, and for investigating the utility of SFN for epigenetically restoring sensitivity of ER- negative cancers to endocrine therapy. We anticipate that data obtained from these studies will be extremely important for informing biomarker selection for clinical studies of SFN for breast cancer prophylaxis. By using broccoli sprouts we emphasize a "whole-food" approach to cancer prevention which may be pertinent in developing evidence-based health recommendations that could significantly reduce the burden of breast cancer. Our proposal is thus highly responsive to several areas of interest defined by PAR-11-079.