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致癌原因。 女性的死亡。这个问题的严重性为研究提供了强大的推动力，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……里面 在这方面，几项研究表明肥胖与乳腺癌的发生呈正相关。现有证据 提出的这一观察机制强烈暗示雌激素受体的参与。 (呃)。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。 乳腺癌的致病因素。此外，服用HMG-CoA还原酶亲脂抑制剂(他汀类)的患者 显示乳腺癌发病率和复发风险降低。最近的观察显示，27- 羟基胆固醇(27HC)是以化学计量方式从胆固醇中产生的，与我们的数据一起 证明它对内质网和肝X受体(LXRs)都有部分激动剂活性，提示 高胆固醇血症与乳腺癌之间潜在的、迄今未被认识到的机制联系 发病率。几个关键证据构成了拟议项目的基础：(1)肥胖、新陈代谢 综合征和高血清胆固醇都与乳腺癌发病率的增加有关。 肿瘤微环境中27HC的主要产生者肿瘤相关巨噬细胞的浓缩 与预后不良有关，以及(3)自发性小鼠模型中27HC水平的升高。 乳腺癌在体内增加了肿瘤的生长和转移。基于这些发现，我们假设 27HC通过对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。我的长期目标是开发一种 独立研究计划侧重于定义胆固醇生物学的操纵，无论是病理上还是 从药理上讲，影响乳腺癌的发生和发展。在高素质人才的帮助下 我选择的导师和咨询委员会成员，以及特殊的研究 在杜克大学医学院的环境中，我非常适合回答这些重要的问题 在这份提案中被问及。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、生长和转移增加之间的关系，(2) 评估了靶向胆固醇和27HC产生的效用，以及相关的下游信号 乳腺癌治疗和预防的途径，以及(3)确定了27HC 增加转移。预计这一调查路线将导致近期内 治疗和预防乳腺癌的新策略。此外，结果可能会提供额外的支持 和探索低胆固醇饮食和/或潜在的化学预防益处的理论基础 HMG-CoA还原酶或CYP27A1的药理抑制剂。

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.