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

Omega-3 脂肪酸与 ERPR(-) 和 HER-2/neu( ) 乳腺癌预防

• 批准号: 9050650
• 负责人: LISA D YEE
• 金额: $ 31.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-13 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050650
• 关键词: Accounting; Adipose tissue; Affect; American; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Applications Grants; Atypia; Behavior; Biological Markers; Blood; Breast; Breast Cancer Prevention; Breast Cancer survivor; Breast Carcinogenesis; Breast Epithelial Cells; Cancer Etiology; Cells; Cessation of life; Clinical; Clinical Trials; Collection; Corn Oil; DNA Methylation; Data; Development; Diet; Dietary Factors; Dietary Fats; Dietary Intervention; Dinoprostone; Disease; Docosahexaenoic Acids; Dose; ERBB2 gene; Eicosapentaenoic Acid; Epigenetic Process; Epithelial; Estrogen Receptors; Fatty Acids; Fine needle aspiration biopsy; Fish Oils; Fishes; Future; GPX3 gene; Gas Chromatography; Gene Expression Profile; Genes; Genetic Markers; Growth; Health; Heterogeneity; High Risk Woman; Hormone Receptor; Human; Hyperplasia; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Intervention; Intervention Trial; Link; Lipids; Literature; Lymph Node Involvement; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Measures; Methodology; Methylation; Molecular Genetics; Molecular Profiling; Mus; Nutrient; Omega-3 Fatty Acids; Outcome; PTEN gene; PTGS2 gene; Placebo Control; Placebos; Polyunsaturated Fatty Acids; Predisposition; Prevention; Prevention strategy; Prevention trial; Primary Prevention; Probability; Progesterone Receptors; Publishing; Randomized; Recurrence; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Secondary Prevention; Signal Transduction; Survivors; TNF gene; Techniques; Time; Tissue Sample; Tissues; Transgenic Mice; Transgenic Organisms; Translations; Woman; arm; base; bioactive food component; biomarker development; cancer diagnosis; cancer subtypes; capsule; carcinogenesis; efficacy testing; eicosanoid metabolism; epigenetic regulation; erbB-2 Receptor; feeding; gene interaction; genetic signature; high risk; improved; indexing; innovation; malignant breast neoplasm; methylation pattern; molecular marker; mouse model; multidisciplinary; novel; novel strategies; nutritional approach; outcome forecast; overexpression; pre-clinical; preclinical study; progesterone receptor negative; prognostic; promoter; prospective; proteomic signature; response; skills; targeted treatment; triple-negative invasive breast carcinoma; tumor

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.

描述（由申请人提供）：尽管经过几十年的基础和临床研究，乳腺癌仍然是导致癌症死亡的第二大原因，也是美国女性中最常见的癌症。预防和治疗方面的一个重大突破是认识到乳腺癌不是一种疾病，而是一种癌症亚型的集合，通过基于组织病理学、遗传和分子特征的改进方法，可以更好地定义癌症亚型。随着时间的推移，我们应用组织学类型、分级、肿瘤大小、淋巴结累及、雌激素受体（ER）和HER-2/新受体状态来帮助确定预后和对治疗反应的可能性，但仅靠这些并不能完全捕获乳腺癌的各种行为。基因表达和蛋白质组学特征正在迅速发展，这将有助于我们对个体进行“个性化”干预。同样的概念也适用于初级或二级预防的干预措施，也是我们的转化资助申请的重点。我们的临床前研究表明，在转基因小鼠模型中，富含ω-3脂肪酸的鱼油对ERPR(-)HER-2/neu（+）乳腺肿瘤有很强的抑制作用，显示出肿瘤发生率、多样性和腺非典型性的降低。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(-)（即三重阴性）疾病，可能对鱼油中发现的长链ω-3多不饱和脂肪酸（PUFAs）二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）有独特的反应。作为未来在女性中进行明确预防试验的第一步，我们建议测试富含ω-3的鱼油补充剂对指示抗癌作用的乳腺生物标志物的调节功效。我们将高风险幸存者随机分配到低剂量或高剂量富含ω-3的鱼油胶囊治疗中，并使用我们的乳房细针抽吸技术获取细胞和组织，以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ω-3脂肪酸对复发性雌激素受体、孕激素受体乳腺癌+/- HER-2/neu过表达高风险女性暴露和反应的生物标志物的影响；(2)确定膳食中ω-3 PUFAs在乳腺癌发生下炎症反应的表观遗传调控中的作用，作为ω-3 PUFAs作用的新机制。这些ω-3 PUFA暴露和反应的生物标志物的开发，将使这种生物活性食品成分在未来对ERPR（-）、HER-2/neu（+）或三阴性乳腺癌复发风险妇女的大规模预防试验中得到评估。