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“自发性”或癌基因诱导的乳腺癌的能力，从而建立一个易于处理的系统，用于SFN介导的乳腺癌抑制的新机制研究。SFN是一种膳食异硫氰酸酯，来源于食用十字花科蔬菜（如西兰花）期间的前体化合物（萝卜硫苷），西兰花是SFN前体的特别丰富来源。与一些观察性研究中确定的十字花科蔬菜摄入量与乳腺癌风险之间的反比关系一致，SFN在实验性乳腺癌模型中具有有效的抗癌活性。具体而言，SFN防止由致癌物处理诱导的啮齿动物乳腺肿瘤，最有可能是由于II期酶诱导和由此产生的致癌物失活加速。然而，最近，一种新的活性已被确定为SFN作为表观遗传调节剂通过抑制组蛋白脱乙酰酶（HDAC）的活性。引人注目的是，SFN已被证明可以改变组蛋白乙酰化状态在体外和体内的小鼠和人类。在这里，我们建议研究SFN使用致癌物独立或“自发性”乳腺癌模型，其中雌激素受体（ER）阴性乳腺肿瘤是由癌基因过表达驱动。这种广泛使用的小鼠模型应该提供一个有用的实验系统，最终评估SFN介导的HDAC抑制的重要性。SFN将以西兰花芽的形式提供，西兰花芽是SFN前体的异常丰富的来源。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是双重的.首先，我们将测试膳食SFN对肿瘤形成、增殖、生长速率和转移的影响。其次，我们将研究SFN介导的调制的生物学终点在小鼠乳腺组织中，使用正常和癌前乳腺组织和乳腺癌。试验将包括：HDAC活性和组蛋白乙酰化状态，II相酶表达，增殖和凋亡。此外，我们将比较对照组和SFN治疗组小鼠肿瘤中的ER表达。这些初步研究将为未来的R 01规模研究奠定基础，以建立观察到的变化和SFN介导的肿瘤保护之间的因果关系，并研究SFN用于表观遗传学恢复ER阴性癌症对内分泌治疗的敏感性的效用。我们预计，从这些研究中获得的数据对于为以下临床研究提供生物标志物选择的信息将非常重要： SFN用于预防乳腺癌。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，这可能与制定基于证据的健康建议有关，可以显着降低乳腺癌的负担。因此，我们的提案高度响应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.