The Role of 27-hydroxycholesterol in Breast Cancer: A Population-Based Multiethnic Study

27-羟基胆固醇在乳腺癌中的作用：基于人群的多种族研究

• 批准号: 10581518
• 负责人: Iona C Cheng
• 金额: $ 42.13万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581518
• 关键词: 27-hydroxycholesterol; Abdomen; Address; Adipose tissue; African American population; Asian Americans; Biochemistry; Biological; Biological Markers; Biometry; Blood; Blood specimen; Body Patterning; Body fat; Body mass index; Body measure procedure; Breast Cancer Prevention; Breast Cancer Risk Factor; Characteristics; Cholesterol; Cohort Studies; Complex; Cross-Sectional Studies; Data; Development; Diagnostic; Dietary Fats; Enzymes; Epidemiology; Estradiol; Estrogen Receptors; Estrogens; Ethnic Origin; Ethnic Population; Fatty acid glycerol esters; Female; Gene Expression; Gene Expression Profile; Genetic; Growth; Health behavior; High Prevalence; Image; Incidence; Inflammation; Intake; Japanese American; Joints; Knowledge; Laboratory Study; Latino Population; Life Style; Link; Lipids; Liver; Longitudinal Studies; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Molecular Biology; Molecular Epidemiology of Cancer; Native Hawaiian; Neoplasm Metastasis; Nested Case-Control Study; Newly Diagnosed; North America; Obesity; Oncology; Outcome; Participant; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Plasma; Postmenopause; Prevention strategy; Progesterone Receptor Status; Prognosis; Prospective Studies; Questionnaires; Race; Receptor Activation; Resources; Role; Sampling; Selective Estrogen Receptor Modulators; Specimen; Testing; Thinness; Tissue Sample; Tumor Tissue; Variant; Visceral; Waist-Hip Ratio; Woman; biobank; cancer therapy; cohort; demographics; epidemiologic data; epidemiology study; ethnic difference; ethnic disparity; ethnic diversity; experience; follow-up; hypercholesterolemia; innovation; lifestyle factors; malignant breast neoplasm; metabolic profile; molecular subtypes; multi-ethnic; multidisciplinary; population based; racial difference; racial disparity; racial diversity; racial population; subcutaneous; treatment strategy; tumor

ABSTRACT Excess overall adiposity (obesity) is one of the most significant risk factors for breast cancer in postmenopausal women and is a key predictor for poor prognosis. Excess central or visceral adiposity, rather than overall or subcutaneous adiposity, is more indicative of abnormal metabolic profiles and is strongly associated with obesity- related outcomes, including breast cancer incidence and prognosis. Postulated mechanisms underlying the association between obesity and post-menopausal breast cancer include higher levels of estradiol, hypercholesterolemia, and inflammation. Laboratory studies established the cholesterol metabolite, 27- hydroxychlolesterol (27HC), as an endogenous selective estrogen receptor modulator capable of promoting breast cancer growth and metastasis. However, epidemiologic data on the role of 27HC in breast cancer incidence and tumor characteristics is lacking, particularly for diverse racial/ethnic populations. Thus, we propose to conduct a large-scale epidemiologic study to examine the associations of 27HC with body fat distribution, breast cancer incidence, and clinicopathologic characteristics among participants of the Multiethnic Cohort (MEC), which includes five major racial/ethnic groups in the U.S.―African Americans, Japanese Americans, Native Hawaiians, Latinos and Whites. In Aim 1, we will examine the association between body fat distribution and circulating levels of 27HC in 913 healthy females and conduct a longitudinal study among a subset of these women (n=796) to examine the association between waist-hip-ratio and circulating levels of 27HC. In Aim 2, we will examine the independent association of circulating levels of 27HC and joint associations of 27HC, estradiol, and lipids with postmenopausal breast cancer incidence (cases/controls=1,572/1,572). In Aim 3, we will examine in breast tumor tissue (n=700) the association between gene expression levels of 27HC-regulating enzymes and clinicopathologic characteristics, including grade, stage, PAM50-defined molecular subtypes, and breast cancer-specific gene expression signatures. The strengths of this proposal include: (1) it represents the first large-scale multiethnic population-based epidemiologic investigation of 27HC and breast cancer; (2) it investigates the possible pathway by which 27HC may impact breast cancer by examining refined measures of body fat distribution in relation to 27HC levels; (3) it examines the relationship between expression of 27HC- regulating enzymes and clinicopathologic characteristics in breast tumors to interrogate the biological mechanisms mediated by 27HC; (4) it leverages the high quality resources within the MEC (e.g. extensive questionnaire information, blood and tumor tissue samples, and >20 years of follow-up data). The findings from this proposal will expand our understanding of the role of the 27HC-estradiol pathway in breast cancer, particularly in regards to different body fat distribution. This knowledge could serve as the basis for personalized breast cancer prevention and treatment strategies across different racial/ethnic populations.

抽象的 整体过度肥胖（肥胖）是绝经后乳腺癌最重要的危险因素之一 女性，是预后不良的关键预测因素。过度的中枢或内脏肥胖，而不是整体或内脏肥胖 皮下脂肪过多，更能表明代谢特征异常，并且与肥胖密切相关 相关结果，包括乳腺癌发病率和预后。假设的机制 肥胖与绝经后乳腺癌之间的关联包括较高水平的雌二醇， 高胆固醇血症和炎症。实验室研究确定了胆固醇代谢物，27- 羟基胆固醇（27HC），作为一种内源性选择性雌激素受体调节剂，能够促进 乳腺癌的生长和转移。然而，关于 27HC 在乳腺癌中的作用的流行病学数据 缺乏发病率和肿瘤特征，特别是对于不同种族/族裔人群。因此，我们建议 进行大规模流行病学研究，以检验 27HC 与身体脂肪分布的关系， 多种族队列参与者的乳腺癌发病率和临床病理特征 (MEC)，其中包括美国的五个主要种族/族裔群体——非裔美国人、日裔美国人、 夏威夷原住民、拉丁裔和白人。在目标 1 中，我们将检查身体脂肪分布之间的关联 913 名健康女性中 27HC 的循环水平，并对其中的一部分进行纵向研究 女性 (n=796) 检查腰臀比与 27HC 循环水平之间的关联。在目标 2 中， 我们将检查 27HC 循环水平的独立关联和 27HC 的联合关联， 雌二醇和血脂与绝经后乳腺癌发病率的关系（病例/对照=1,572/1,572）。在目标 3 中，我们 将检查乳腺肿瘤组织 (n=700) 27HC 调节基因表达水平之间的关联 酶和临床病理特征，包括分级、阶段、PAM50 定义的分子亚型，以及 乳腺癌特异性基因表达特征。该提案的优点包括：（1）它代表了 首次针对 27HC 和乳腺癌进行大规模多种族流行病学调查； (2)它 通过检查 27HC 影响乳腺癌的可能途径 体脂肪分布与 27HC 水平的关系； (3)考察27HC-表达之间的关系 调节乳腺肿瘤中的酶和临床病理特征以探究其生物学特性 27HC 介导的机制； (4)利用MEC内部的优质资源（例如广泛的 问卷信息、血液和肿瘤组织样本以及超过 20 年的随访数据）。研究结果来自 该提案将扩大我们对 27HC-雌二醇途径在乳腺癌中的作用的理解， 特别是关于不同的身体脂肪分布。这些知识可以作为个性化的基础 不同种族/民族人群的乳腺癌预防和治疗策略。