Dietary lignan effects on hormone, growth, and signaling factors in breast tumors

描述（由申请人提供）：几项流行病学研究表明，高剂量摄入木脂素与降低乳腺癌风险有关。最近，我们和其他研究人员进一步表明，高摄入量的女性患雌激素受体（ER）阴性乳腺癌的风险比低摄入量的女性低，这表明雌激素的保护作用可能对某些亚型的癌症更有效。雌激素受体状态以及其他一些肿瘤特征与乳腺癌预后有关。尽管实验证据支持膳食木脂素对许多肿瘤标志物有有利影响的潜力，但许多实验室工作都使用了亚麻籽中木脂素的药理学剂量。除了关于木脂素摄入量和内质网状态的有限数据外，还没有进行关于膳食木脂素摄入量通常范围对其他预后和预测肿瘤特征的影响的研究。在大豆摄入量普遍较低的西方人群中，木脂素构成了植物雌激素摄入量的最大贡献，摄入量可以根据所食用的食物而有很大的差异。广泛的可能摄入量是很重要的，因为实验证据表明，植物雌激素的作用往往是浓度依赖的，目前尚不清楚通过饮食摄入的量是否能产生与膳食补充剂的药理学剂量相同的效果。阐明多种植物雌激素水平的影响对于充分理解木脂素摄入影响肿瘤生长和发展的机制是必要的。罗斯威尔公园癌症研究所（RPCI）为癌症相关研究开发了一个核心资源。数据库和生物库（DBBR）是一个包含生物标本和相关临床和流行病学数据的综合信息和样本库。数据和生物标本由患有癌症或有癌症风险的RPCI患者及其陪伴的家人和朋友捐赠。RPCI的乳腺诊所积极将患者纳入DBBR，每年约有300名女性乳腺癌患者。大多数DBBR参与者可获得肿瘤组织，大多数还提供广泛的流行病学数据，包括详细的食物频率问卷。在这一独特而丰富的资源框架内，我们建议对饮食木脂素摄入量与乳腺癌预后相关的一些肿瘤特征进行调查。使用500名参加DBBR的女性的组织块，以及DBBR食物频率问卷中膳食木脂素摄入量的测量，我们将评估以下具体目标：1)检查与木脂素摄入量相关的肿瘤增殖（Ki-67）、细胞凋亡（caspase）和肿瘤生长（Ki-67:caspase比率）率；2)检测生长因子和信号通路蛋白表达（ERa、ER¿、ERa: ER¿比值、PgR、HER2、IGF1、IGFIR）与膳食木脂素摄入量的关系；3)检查乳腺肿瘤亚型（管腔A、管腔B、HER2和基底样）与饮食木脂素摄入量的关系。我们还将通过年龄、体重指数、生殖史、营养摄入和其他相关数据来研究膳食木脂素摄入量与肿瘤特征之间关系的潜在改变。木脂素是一种植物化合物，可以作为激素或通过其他机制限制癌症的生长。这项拟议的研究将调查膳食木脂素摄入量（通常在日常饮食中摄入的量）与几种激素和生长相关的肿瘤特征（其中许多与乳腺癌预后有关）之间的关系。这项研究的结果可能为我们提供了重要的信息，可以帮助我们了解饮食对不同乳腺癌亚型发展的影响。

DESCRIPTION (provided by applicant): Several epidemiologic studies have shown reduced breast cancer risks associated with higher exposure to dietary lignans. Recently, we and others have further shown reduced risks of estrogen receptor (ER) negative breast cancer in women with high versus low dietary intakes, suggesting that the protective effects might be more effective in certain sub-types of cancer. ER status, as well as a number of other tumor characteristics, has been associated with breast cancer prognosis. Although experimental evidence supports the potential for dietary lignans to favorably affect many of these tumor markers, much of the laboratory work has used pharmacologic doses of lignans from flaxseed. Besides the limited data regarding lignan intakes and ER status, an examination of the effect of commonly consumed ranges of dietary lignan intakes on other prognostic and predictive tumor characteristics has not been conducted. Lignans constitute the largest contribution to phytoestrogen intakes among Western populations where soy intake is generally low, and intakes can range widely depending upon which foods are consumed. The wide range of possible intakes is important as experimental evidence suggests that phytoestrogen actions often are concentration dependent, and it is unclear whether amounts consumed via diet produce the same effects as pharmacologic doses available as dietary supplements. Elucidation of the effects of a wide range of phytoestrogen levels is necessary to adequately understand the mechanisms by which lignan intake can affect tumor growth and development. Roswell Park Cancer Institute (RPCI) has developed a core resource for cancer related research. The Data Bank and Biorepository (DBBR) is a comprehensive information and sample bank containing biospecimens and associated clinical and epidemiologic data. The data and biospecimens are donated by RPCI patients who have cancer, or who are at risk for cancer, and their accompanying family and friends. The Breast Clinic at RPCI actively enrolls patients into the DBBR with accruals of approximately 300 women with breast cancer per year. Tumor tissue is available for the majority of the DBBR participants, and a majority also provides extensive epidemiologic data, including a detailed food frequency questionnaire. Within the framework of this unique and rich resource, we propose to conduct an investigation of dietary lignan intakes with a number of tumor characteristics associated with prognosis in breast cancer. Using tissue blocks from 500 women with incident, primary, histologically-confirmed invasive breast cancer enrolled in the DBBR, and measures of dietary lignan intakes from the DBBR food frequency questionnaire, we will evaluate the following specific aims: 1) examine tumor proliferation (Ki-67), apoptosis (caspase), and tumor growth (Ki- 67:caspase ratio) rates associated with lignan intakes; 2) examine growth factor and signaling pathway protein expression (ERa, ER¿, ERa: ER¿ ratio, PgR, HER2, IGF1, IGFIR) associated with dietary lignan intakes; and 3) examine the association of breast tumor subtype (luminal A, luminal B, HER2, and basal-like) with dietary lignan intakes. We will also investigate the potential modification of the associations between dietary lignan intakes and tumor characteristics by characteristics such as age, body mass index, reproductive history, nutrient intakes, and other related data. Lignans are plant compounds that can act as hormones or restrict cancer growth through other mechanisms. The proposed study will investigate the association of dietary lignan intakes, as amounts commonly consumed in usual diets, with several hormone and growth-related tumor characteristics, many of which are related to breast cancer prognosis. The results of this study may provide us with important information that can be useful in understanding the effect of diet on development of different breast cancer sub-types.