Isothiocyanate-Mediated Breast Cancer Prevention

描述(申请人提供)：这项研究的主要目标是测试饮食中萝卜硫素(SFN)预防“自发性”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易于处理的系统。SFN是一种饮食中的异硫氰酸酯，来自食用十字花科蔬菜时的前体化合物(葡萄糖萝卜素)，西兰花是SFN前体的特别丰富的来源。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之间的反向关系一致，SFN在实验性乳腺癌模型中具有强大的抗癌活性。具体地说，SFN可以防止致癌物处理引起的啮齿动物乳腺肿瘤，这很可能是由于II期酶诱导和由此导致的致癌物失活加速的结果。然而，最近，通过抑制组蛋白脱乙酰酶(HDAC)活性，SFN作为表观遗传调节剂被发现具有新的活性。引人注目的是，SFN已经被证明在体外和体内改变了小鼠和人类的组蛋白乙酰化状态。在这里，我们建议使用非致癌物或“自发性”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度表达驱动的。这种广泛使用的小鼠模型应该提供一个有用的实验系统，在其中最终评估SFN介导的HDAC抑制的重要性。SFN将以花椰菜芽的形式提供，这是SFN前体的一种异常丰富的来源。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乳腺癌和前列腺癌患者的西兰花芽SFN。这里提出的这项研究的目标有两个。首先，我们将测试饲料中SFN对肿瘤的形成、增殖、生长速度和转移的影响。其次，我们将以正常乳腺组织、癌前病变组织和乳腺癌为研究对象，研究SFN对小鼠乳腺组织中生物端点的调节作用。检测内容包括：HDAC活性和组蛋白乙酰化状态、II相酶表达、细胞增殖和细胞凋亡。此外，我们还将比较对照组和SFN处理组小鼠肿瘤中ER的表达。这些先导性研究将为未来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联系，并研究SFN在恢复ER阴性癌症对内分泌治疗的表观遗传学敏感性方面的应用。我们预计，从这些研究获得的数据将是极其重要的，为临床研究提供生物标志物的选择。 三氟化钠用于乳腺癌预防。通过使用西兰花芽，我们强调了一种“全食物”的癌症预防方法，这可能与开发基于证据的健康建议有关，从而显著减轻乳腺癌的负担。因此，我们的建议非常符合PAR-11-079定义的几个感兴趣的领域。

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.