Omega-3 fatty acids and ERPR(-) and HER-2/neu(+) breast cancer prevention

项目摘要 尽管经过了几十年的基础和临床研究，乳腺癌仍然是第二大致癌原因。 死亡和美国女性最常被诊断出的癌症。预防工作的重大突破 治疗方法是认识到乳腺癌不是一种疾病，而是一组癌症 通过基于组织病理学、遗传学和免疫组化的改进方法更好地定义亚型 分子签名。随着时间的推移，我们应用了组织学类型、分级、肿瘤大小、淋巴结 雌激素受体(ER)和HER-2/neu受体状态有助于确定预后和 治疗反应的概率，但仅靠这些并不能完全捕捉到乳房的不同行为 癌症。这一领域现在正在迅速发展，基因表达和蛋白质组签名将有助于 “个性化”我们针对个人的干预措施。同样的概念也适用于初级或初级保健干预。 二级预防，这是我们转换拨款申请的重点。我们的临床前研究已经 富含-3脂肪酸的鱼油对ERPR(-)HER-2/neu(+)有很强的抑制作用 转基因小鼠乳腺肿瘤的发病率、多发性和腺性降低 非典型性。因此，我们的中心假设是侵袭性乳腺癌亚型的发展，如 ERPR(-)HER-2/neu(+)或ERPR(-)Her-2/neu(-)(即三重阴性)疾病可能对 二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)，长链-3多不饱和脂肪酸 (多不饱和脂肪酸)在鱼油中发现。作为迈向未来妇女最终预防试验的第一步，我们建议 富含AN-3鱼油的补充剂对乳房抗癌生物标志物的调节作用 行动。我们将把高危幸存者随机分为安慰剂低剂量和高剂量富含鱼油胶囊。 治疗并使用我们的乳房细针抽吸技术获得细胞和组织用于分析 暴露和疗效的生物标志物。我们的多学科团队制定了以下具体目标： (1)确定饮食中-3脂肪酸对处于高水平的女性暴露和反应的生物标志物的影响 雌激素受体、孕激素受体乳腺癌+/-HER-2/neu过度表达的风险；以及 (2)明确膳食-3多不饱和脂肪酸在炎症反应表观遗传调控中的作用 乳腺癌是-3多不饱和脂肪酸作用的新机制。这些方面的发展 多不饱和脂肪酸暴露和反应的生物标志物将使这种生物活性食品成分的评估成为可能 在未来针对有ERPR(-)、HER-2/neu(+)或三重复发风险的妇女的大规模预防试验中 阴性乳腺癌。

Project Summary In spite of decades of basic and clincial research, breast cancer remains the second leading cause of cancer death and the most commonly diagnosed cancer in American women . A major breakthrough for prevention and cure has been the appreciation that breast cancer is not one disease, rather a collection of cancer subtypes becoming better defined by improved methodologies based upon histopathologic, genetic and molecular signatures. Over time we have applied histological type, grade, tumor size, lymph-node involvement, and estrogen receptor (ER) and HER-2/neu receptor status to help define prognosis and probability of response to therapies, yet these alone have not fully captured the varied behavior of breast cancer. The field is now rapidly progressing with gene expression and proteomic signatures that will help "personalize" our interventions for individuals. This same concept is relevant to interventions for primary or secondary prevention and is the focus of our translational grant application. Our pre-clinical studies have demonstrated a strong benefit for dietary -3 fatty acid rich fish oil for the inhibition of ERPR(-)HER-2/neu(+) mammary tumors in a transgenic mouse model showing decreased tumor incidence, multiplicity and glandular atypia. Thus, our central hypothesis is that the development of aggressive breast cancer sub-types such as of ERPR(-)HER-2/neu(+) or ERPR(-)HER-2/neu(-) (i.e. triple negative) disease may be uniquely responsive to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the long chain -3 polyunsaturated fatty acids (PUFAs) found in fish oil. As a first step towards a future definitive prevention trial in women, we propose to test the efficacy of an -3 rich fish oil supplement to modulate breast biomarkers indicative of anti-carcinogenic action. We will randomize high risk survivors to a placebo-low dose or high dose -3 rich fish oil capsule treatment and employ our breast fine needle aspiration techniques to obtain cells and tissue for analysis of biomarkers of exposure and efficacy. Our multidisciplinary team has developed the following Specific Aims to: (1) Determine the effects of dietary -3 fatty acids on biomarkers of exposure and response in women at high risk for recurrent estrogen receptor, progesterone receptor breast cancer +/- HER-2/neu overexpression; and (2) Define the role of dietary -3 PUFAs in the epigenetic regulation of the inflammatory responses underlying mammary carcinogenesis as a novel mechanism for the effects of -3 PUFAs. Development of these biomarkers of -3 PUFA exposure and response will enable the assessment of this bioactive food component in future large-scale prevention trials for women at risk for recurrence of ERPR(-)HER-2/neu(+) or triple negative breast cancer.