Impact of cholesterol and its metabolites on breast cancer progression

项目摘要 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- 与女性有关的死亡。相关的死亡率最常是由于转移性疾病。这件事的重要性 这一问题为研究提供了强大的动力，这些研究可能导致新的化学预防药物的开发。 策略和/或生活方式的改变，以预防和治疗癌症转移。在这方面，流行病学研究 发现循环胆固醇升高是乳腺癌转移的危险因素。另一方面，在一项研究中， 服用HMG-CoA还原酶抑制剂（他汀类）的患者显示出增加的无复发生存期。的 观察到胆固醇的主要代谢物27-羟基胆固醇的循环浓度 （27 HC）与胆固醇相关，以及这种代谢物可以作为 雌激素受体（ER）和肝X受体（LXR）的配体，提示了一种潜在的机制， 高胆固醇血症和乳腺癌转移之间的联系。事实上，我们已经发现，27 HC有力地 在几种乳腺癌小鼠模型中增加转移，而在缺乏 合成27 HC的能力。有趣的是，我们发现27 HC的促转移作用是由于 影响宿主免疫系统的能力此外，从免疫细胞释放的细胞外囊泡 用27 HC处理的具有促转移特性。然而，精确的受体介导的机制， 27 HC影响免疫细胞或细胞外囊泡货物仍然未知。我们假设27 HC 通过选择性调节ER和LXR改变免疫微环境， 增加远端部位的癌细胞定植。我们将系统地测试这一假设（1）识别 负责27 HC作用的受体介导机制，包括确定选择性 不同氧化固醇对ER和LXR的调节，（2）评估27 HC调节ER和LXR的机制。 细胞外囊泡的货物和释放，以及（3）阐明27 HC影响免疫的机制 细胞以促进转移。一系列的综合实验将确定细胞和生化 27 HC促进转移的机制。这些信息将确定最佳方法， 靶向免疫细胞内的ER和LXR轴，这是最近启动的临床研究的重要信息。 针对这些受体的试验。预计这一调查路线将导致近期 发展治疗和预防转移性乳腺癌的新策略。本研究具有重要意义 重要的是，鉴于高胆固醇血症的高患病率， ER和LXR，并且与乳腺癌相关的大多数（>90%）死亡率是由于转移性 疾病

PROJECT SUMMARY Despite increased survivorship among patients, breast cancer remains the second leading cause of cancer- related death in women. Associated mortality is most often due to metastatic disease. 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 to prevent and treat cancer metastasis. In this regard, epidemiologic studies have found that elevated circulating cholesterol is a risk factor for breast cancer metastasis. On the other hand, patients taking inhibitors of HMG-CoA reductase (statins) demonstrate increased recurrence free survival. The observation that the circulating concentrations of a primary metabolite of cholesterol, 27-hydroxycholesterol (27HC), are correlated with those of cholesterol, together with the knowledge that this metabolite can serve as a ligand for both the estrogen receptors (ERs) and liver X receptors (LXRs), suggests a potential mechanistic link between hypercholesterolemia and breast cancer metastasis. Indeed, we have found that 27HC robustly increases metastasis in several murine models of mammary cancer, while metastasis is reduced in mice lacking the capacity to synthesize 27HC. Intriguingly, we have found that the pro-metastatic effects of 27HC are due to its ability to impact the host immune system. Furthermore, extracellular vesicles released from immune cells treated with 27HC possess pro-metastatic properties. However, the precise receptor-mediated mechanisms by which 27HC influences immune cells or extracellular vesicle cargo remain unknown. We hypothesize that 27HC alters the immune micro-environment via selective modulation of the ERs and LXRs culminating in the increased cancer cell colonization of distal sites. We will systematically test this hypothesis by (1) identifying the receptor-mediated mechanisms responsible for the actions of 27HC including the determination of selective modulation of the ERs and LXRs by different oxysterols, (2) evaluating the mechanisms by which 27HC regulates extracellular vesicle cargo and release, and (3) elucidating the mechanisms by which 27HC influences immune cells to facilitate metastasis. A series of integrated experiments will determine both the cellular and biochemical mechanisms behind the 27HC promotion of metastasis. This information will determine the best approaches for targeting the ER and LXR axes within immune cells, important information given the recently initiated clinical trials targeting these receptors. It is anticipated that this line of investigation will lead to the near-term development of new strategies to treat and prevent metastatic breast cancer. This research is of significant importance, given the high prevalence of hypercholesterolemia, stark differences in the effects of ligands for the ERs and LXRs, and that the majority (>90%) of mortality associated with breast cancer is due to metastatic disease.