Impact of cholesterol and its metabolites on breast cancer progression

项目总结 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。 女性的相关死亡。相关死亡最常见的原因是转移性疾病。这件事的严重性 问题为可能导致新化学预防药物开发的研究提供了强大的推动力 预防和治疗癌症转移的策略和/或生活方式的改变。在这方面，流行病学研究 发现循环中胆固醇升高是乳腺癌转移的风险因素。另一方面， 服用HMG-CoA还原酶抑制剂(他汀类)的患者显示无复发生存率增加。这个 观察到胆固醇的主要代谢物27-羟基胆固醇的循环浓度 (27HC)，与胆固醇的代谢相关，以及这种代谢物可以作为 雌激素受体(ER)和肝脏X受体(LXRs)的配体暗示了一种潜在的机制 高胆固醇血症与乳腺癌转移之间的联系。事实上，我们已经发现27HC的强势 在几种乳腺癌小鼠模型中增加转移，而在缺乏转移的小鼠中转移减少 合成27HC的能力。有趣的是，我们发现27HC的促转移作用是由于 其影响宿主免疫系统的能力。此外，免疫细胞释放的胞外小泡 经27HC处理的肿瘤具有促转移特性。然而，精确的受体介导的机制通过 哪些27HC影响免疫细胞或细胞外小泡货物尚不清楚。我们假设27HC 通过选择性地调节ER和LXRs来改变免疫微环境，最终导致 癌细胞在远端部位的定植增加。我们将通过以下方式系统地检验这一假设：(1)确定 受体介导的27HC的作用机制，包括选择性 不同氧合甾醇对ER和LXRs的调节作用：(2)27HC的调节机制 细胞外囊泡运输和释放；(3)27HC影响免疫的机制 促进转移的细胞。一系列综合实验将确定细胞和生化 27HC促进转移的机制。这些信息将确定用于 针对免疫细胞内的ER和LXR轴，考虑到最近启动的临床试验的重要信息 针对这些受体的试验。预计这条调查路线将导致近期 开发治疗和预防转移性乳腺癌的新策略。这项研究具有重要意义。 重要的是，鉴于高胆固醇血症的高流行率，配体对 ERS和LXR，大多数(90%)与乳腺癌相关的死亡是由转移引起的 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.