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

描述(申请人提供)：尽管经过几十年的基础和临床研究，乳腺癌仍然是美国女性癌症死亡的第二大原因和最常见的诊断癌症。预防和治疗的一个重大突破是认识到乳腺癌不是一种疾病，而是通过基于组织病理学、遗传学和分子签名的改进方法更好地定义癌症亚型的集合。随着时间的推移，我们应用了组织学类型、分级、肿瘤大小、淋巴转移、雌激素受体(ER)和HER-2/neu受体状态来帮助确定预后和治疗反应的可能性，但仅凭这些并不能完全反映乳腺癌的不同行为。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我们对个人的干预“个性化”。这一概念与一级或二级预防干预措施有关，也是我们转化性赠款申请的重点。我们的临床前研究表明，在转基因小鼠模型中，饮食中富含ω-3脂肪酸的鱼油对抑制ERPR(-)HER-2/neu(+)乳腺肿瘤具有很强的益处，显示出肿瘤发生率、多样性和腺体异型性的降低。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(-)(即三阴性)疾病可能是唯一对二十碳五烯酸和二十二碳六烯酸的反应，这两种长链ω-3多不饱和脂肪酸存在于鱼油中。作为未来女性明确预防试验的第一步，我们建议测试富含ω-3的鱼IL补充剂对指示抗癌作用的乳房生物标记物的调节效果。我们将随机对高危幸存者进行安慰剂低剂量或高剂量ω-3富含鱼油胶囊治疗，并使用我们的乳房细针抽吸技术获取细胞和组织，用于分析暴露和疗效的生物标志物。我们的多学科团队已制定了以下具体目标：(1)确定膳食ω-3脂肪酸对复发雌激素受体、孕激素受体乳腺癌+/-HER-2/neu过度表达的高危女性暴露和反应的生物标志物的影响；以及(2)确定膳食ω-3多不饱和脂肪酸在乳腺癌发生背后的炎症反应的表观遗传调控中的作用，作为ω-3多不饱和脂肪酸作用的新机制。这些ω-3多不饱和脂肪酸暴露和反应生物标志物的开发将使在未来针对有复发风险的妇女的大规模预防试验中能够评估这种生物活性食品成分，这些妇女有复发的风险，HER-2/neu(+)或三阴性乳腺癌。

DESCRIPTION (provided by applicant): 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 ω-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 ω-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 ω-3 rich fish il supplement to modulate breast biomarkers indicative of anti-carcinogenic action. We will randomize high risk survivors to a placebo-low dose or high dose ω-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 ω-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 ω-3 PUFAs in the epigenetic regulation of the inflammatory responses underlying mammary carcinogenesis as a novel mechanism for the effects of ω-3 PUFAs. Development of these biomarkers of ω-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.