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

描述(申请人提供)：尽管患者的存活率增加，乳腺癌仍然是女性癌症死亡的第二大原因。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的研究提供了强大的推动力。在这方面，几项研究表明肥胖与乳腺癌的发生呈正相关。目前的证据和提出的这一观察机制强烈暗示雌激素受体(ER)的参与。重要的是，肥胖也与胆固醇升高高度相关，而胆固醇本身就是乳腺癌的风险因素。此外，患者服用HMG-CoA还原酶(他汀类)的亲脂性抑制剂(他汀类)可降低乳腺癌发病率和复发的风险。最近的观察表明，27-羟基胆固醇(27HC)是由胆固醇以化学计量方式产生的，再加上我们的数据表明，它对ER和肝X受体(LXRs)都具有部分激动剂活性，这表明高胆固醇血症与乳腺癌发病率之间存在潜在的、迄今尚未被认识的机制联系。几个关键证据构成了该项目的基础：(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)肿瘤相关巨噬细胞--27HC的主要产生者--在肿瘤微环境中的丰富与预后不良有关，(3)在自发性乳腺癌的小鼠模型中，27HC水平的升高增加了体内肿瘤的生长和转移。基于这些发现，我们假设27HC通过对ER和LXR的作用，是肥胖、高胆固醇血症和乳腺癌发病率增加之间的重要机制联系。我的长期目标是开发一个独立的研究计划，专注于确定胆固醇生物学的操纵，无论是从病理上还是从药物上，都会如何影响乳腺癌的发生和发展。在我挑选的高素质导师和咨询委员会成员的帮助下，加上杜克大学医学院特殊的研究环境，我非常适合回答这项提案中提出的重要问题。在本项目结束时，我希望(1)建立肥胖、胆固醇与乳腺癌易感性增加、生长和转移之间的机制联系，(2)评估靶向胆固醇和27HC产生的效用，以及相关的下游信号通路在乳腺癌治疗和预防中的作用，以及(3)确定27HC增加转移的机制。预计这项研究将导致近期开发新的治疗和预防乳腺癌的策略。此外，这些结果可能会为探索低胆固醇饮食和/或HMG-CoA还原酶或CYP27A1的药理抑制剂的潜在化学预防益处提供额外的支持和理论基础。

DESCRIPTION (provided by applicant): 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 takin 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.