27-hydroxycholesterol as a link between obesity and breast cancer pathogenesis

摘要 尽管患者的存活率有所提高，但乳腺癌仍然是第二大癌症原因 女人的死亡这一问题的严重性为可能导致 开发新的化学预防策略和/或改变生活方式以降低癌症发病率。在 在这方面，一些研究表明肥胖与乳腺癌的发生呈正相关。目前的证据 这一观察结果的机制强烈暗示了雌激素受体的参与， （ER）。重要的是，肥胖也与胆固醇升高高度相关，而胆固醇本身就是一种风险 乳腺癌的危险因素。此外，服用亲脂性HMG-CoA还原酶抑制剂（他汀类药物）的患者 证明乳腺癌发病率和复发的风险降低。最近的观察显示，27- 羟基胆固醇（27 HC）是由胆固醇以化学计量的方式产生的，连同我们的数据 表明它对ER和肝脏X受体（LXR）都具有部分激动剂活性，表明 高胆固醇血症和乳腺癌之间潜在的、迄今未被认识的机制联系 发病率。几个关键的证据构成了拟议项目的基础：（1）肥胖，代谢 综合征和高血清胆固醇都与乳腺癌发病率增加有关，（2） 肿瘤微环境中肿瘤相关巨噬细胞（27 HC的主要生产者）的富集 与不良预后相关，以及（3）自发性肝硬化小鼠模型中27 HC水平升高 乳腺癌增加体内肿瘤生长和转移。基于这些发现，我们假设 27 HC通过其对ER和LXR的作用，是肥胖之间的重要机制联系， 高胆固醇血症和乳腺癌发病率增加。我的长期目标是发展一个 一项独立的研究计划，重点是确定如何操纵胆固醇生物学，病理学或 乳腺癌的发生和发展有着密切的关系。在高素质专家的帮助下 导师和咨询委员会成员，我已经选择，沿着的特殊研究 在杜克大学医学院的环境中，我非常适合解决重要的问题 在这个提案中，在这个项目结束时，我希望有（1）建立机械联系 肥胖、胆固醇与乳腺癌易感性、生长和转移之间的关系，（2） 评估了靶向胆固醇和27 HC产生以及相关下游信号传导的效用 乳腺癌的治疗和预防途径，（3）定义了27 HC 增加转移。预计这一调查路线将导致近期的发展， 治疗和预防乳腺癌的新策略。此外，这些结果可能会提供额外的支持， 以及探索低胆固醇饮食的潜在化学预防益处的理由和/或 HMG-CoA还原酶或CYP 27 A1的药理学抑制剂。

Abstract Despite increased survivorship among patients, breast cancer remains the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for studies that may lead to the development of new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. In this regard, several studies positively correlate obesity to the development of breast cancer. Current evidence and proposed mechanisms for this observation strongly implicate the involvement of the estrogen receptor (ER). Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking lipophilic inhibitors of HMG-CoA reductase (statins) demonstrate a decreased risk for breast cancer incidence and recurrence. The recent observation that 27- hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our data demonstrating that it exerts partial agonist activity on both the ERs and liver X receptors (LXRs), suggests a potential, heretofore unrecognized, mechanistic link between hypercholesterolemia and breast cancer incidence. Several key pieces of evidence form the foundation of the proposed project: (1) obesity, metabolic syndrome and high serum cholesterol are all associated with increased breast cancer incidence, (2) enrichment of tumor-associated macrophages, the primary producers of 27HC, in the tumor microenvironment is associated with a poor prognosis, and (3) elevation of 27HC levels in a murine model of spontaneous mammary cancer increases tumor growth and metastasis in vivo. Building on these findings we hypothesize that 27HC, through its actions on ER and LXR, is an important mechanistic link between obesity, hypercholesterolemia and increased incidence of breast cancer. My long-term goal is to develop an independent research program focused on defining how manipulation of cholesterol biology, pathologically or pharmacologically, impacts the initiation and progression of breast cancer. With the help of the highly qualified mentors and advisory committee members that I have selected, along with the exceptional research environment at Duke University School of Medicine, I am very well situated to address the important questions being asked in this proposal. At the conclusion of this project I expect to have (1) established mechanistic links between obesity, cholesterol and increased susceptibility, growth and metastasis of breast cancer, (2) evaluated the utility of targeting cholesterol and 27HC production, and relevant downstream signaling pathways in the treatment and prevention of breast cancer, and (3) defined the mechanisms by which 27HC increases metastasis. It is anticipated that this line of investigation will lead to the near-term development of new strategies to treat and prevent breast cancer. Furthermore, the results will likely provide additional support and rationale for the exploration of potential chemopreventative benefits of lower cholesterol diets and/or pharmacological inhibitors of HMG-CoA reductase or CYP27A1.