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

摘要 过度肥胖(肥胖)是绝经后患乳腺癌的最重要的危险因素之一 并且是预后不良的关键预测因子。中枢或内脏过度肥胖，而不是全面或 皮下肥胖，更多地表明代谢异常，并与肥胖密切相关- 相关结果，包括乳腺癌发病率和预后。潜在的假设机制 肥胖与绝经后乳腺癌之间的关系包括雌激素水平较高， 高胆固醇血症和炎症。实验室研究确定了胆固醇代谢物27- 作为一种内源性选择性雌激素受体调节剂，可促进 乳腺癌的生长和转移。然而，关于27HC在乳腺癌中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/民族的人群。因此，我们建议 进行一项大规模的流行病学研究，研究27HC与体脂分布的关系， 多民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/民族群体-非洲裔美国人，日裔美国人， 夏威夷原住民、拉丁裔和白人。在目标1中，我们将研究身体脂肪分布与 和913名健康女性的循环27HC水平，并在其中一组人中进行纵向研究 妇女(n=796)检查腰臀比和循环27HC水平之间的关系。在目标2中， 我们将研究27HC循环水平的独立关联和27HC的联合关联， 雌激素、血脂与绝经后乳腺癌发病率(病例/对照=1,572/1,572)。在目标3中，我们 将研究乳腺肿瘤组织(n=700)中27HC调节基因表达水平之间的关系 酶和临床病理特征，包括分级、分期、PAM50定义的分子亚型和 乳腺癌特异性基因表达特征。这项建议的优点包括：(1)它代表了 首次对27HC和乳腺癌进行大规模多民族人群流行病学调查； 研究27HC可能影响乳腺癌的可能途径，通过检查改进的 体脂分布与27HC水平的关系；(3)检测27HC-1的表达与 调节酶与乳腺肿瘤临床病理特征探讨其生物学意义 由27HC协调的机制；(4)它利用MEC内的优质资源(例如，广泛的 问卷资料、血液和肿瘤组织样本，以及20年的随访数据)。调查结果来自 这一建议将扩大我们对27HC-雌二醇途径在乳腺癌中的作用的理解， 特别是在不同的体脂分布方面。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战略。

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.