Intestinal phosphatidylcholine exposure and breast cancer risk

 描述(申请人提供)：依赖饮食的肥胖是许多癌症的危险因素，包括绝经后乳腺癌。在乳腺癌患者中，肥胖也与更具侵袭性的乳腺癌亚型和更差的临床结果有关。绝经后乳腺癌患者超重和肥胖的发病率越来越高，这使得确定肥胖与乳腺癌风险和预后之间的这种联系的机制至关重要。更好地了解饮食、肥胖和乳腺癌风险之间的联系，可能会改善肥胖或超重患者的健康营养，或者确定乳腺癌风险评估的标志或药物干预的目标，以降低与肥胖相关的乳腺癌风险。这个K01应用程序的目的是支持先进的质谱学/代谢组学和临床前模型方面的指导培训，使我能够成为一名在肥胖和癌症研究之间工作的独立研究员。解释肥胖和癌症风险之间联系的一个广泛的假设是，高脂肪饮食的消费和/或脂肪合成和储存的增加与生物活性脂类或脂类分子的产生有关，后者本身就会促进疾病。我建议通过促进磷脂衍生的生物活性脂质溶血磷脂酸(LPA)的合成来研究肠道暴露于磷脂磷脂酰胆碱(PC)构成饮食和乳腺癌风险之间的联系的可能性。乳腺癌细胞对LPA有强烈的反应，LPA在体外刺激它们的迁移、生长和存活。LPA合成和信号转导的遗传和药理学靶向减轻小鼠模型中乳腺癌肿瘤的生长和转移。我们认为，饮食中摄入富含PC的食物或将PC作为胆汁分泌到胃中作为对脂肪餐的反应，会导致这种脂类的摄取，作为其Lyso衍生物，LysoPC(LPC)作为肠源性脂蛋白的组成部分在血液中运输，其中LPC是由分泌的溶血磷脂酶D，自体趋化蛋白产生LPA的底物。为了支持这一观点，我们证明了小鼠和人类的血浆LPA水平对禁食和重新喂养非常敏感，在小鼠中，饮食中的PC可以在血液中转化为LPA。为了解决我们的假设，我们将使用质谱学来监测小鼠饮食中PC的代谢，并开发具有明确PC组成的小鼠饮食，我们认为这将导致血浆LPA水平的变化。这一目的中的信息将被用来确定饮食PC的操纵和LPA生成酶自动趋化素的药理抑制对小鼠乳腺癌模型转移的影响。这些研究的完成将提供关于特定饮食成分如何促进人类乳腺癌转移的重要新信息，并可能为未来的翻译研究提供动力，探索药物抑制LPA合成和信号转导的可能性可能成为降低人类乳腺癌风险的可行策略，特别是在肥胖受试者中。

 DESCRIPTION (provided by applicant): Diet-dependent obesity is a risk factor for many cancers including postmenopausal breast cancer. Obesity is also associated with more aggressive breast cancer subtypes and poorer clinical outcomes in breast cancer patients. The increasing prevalence of overweight and obese postmenopausal breast cancer patients makes it critical to identify the mechanisms that underlie this link between obesity and breast cancer risk and prognosis. A better understanding of the link between diet, obesity and breast cancer risk might then lead to improvements in healthful nutrition for obese or overweight patients or identify markers for breast cancer risk assessment or targets for pharmacological intervention to mitigate breast cancer risk associated with obesity. The aim of this K01 application is to support mentored training in advanced mass spectrometry/metabolomics and preclinical models that will enable me to become an independent investigator working at the interface of obesity and cancer research. A broad hypothesis to explain the link between obesity and cancer risk is that consumption of a high fat diet and/or increased synthesis and storage of fats is associated with the production of bioactive lipids or lipid-derived molecules that themselves promote disease. I propose to investigate the possibility that intestinal exposure to the phospholipid phosphatidylcholine (PC) constitutes a link between diet and breast cancer risk by promoting the synthesis of a PC derived bioactive lipid, lysophosphatidic acid (LPA). Breast cancer cells are acutely responsive to LPA which stimulates their migration, growth and survival in vitro. Genetic and pharmacological targeting of LPA synthesis and signaling attenuate breast cancer tumor growth and metastasis in mouse models. We propose that dietary consumption of foods rich in PC or secretion of PC into the stomach as bile in response to a fatty meal results in uptake of this lipid as its lyso derivative, lysoPC (LPC) that is transported in the blood as a component of intestinally derived lipoproteins where is serves as a substrate for production of LPA by the secreted lysophospholipase D, autotaxin. In support of this idea, we show that plasma LPA levels in mice and humans are acutely sensitive to fasting and re-feeding and that, in mice, dietary PC can be converted to LPA in the blood. To address our hypothesis, we will use mass spectrometry to monitor metabolism of dietary PC in mice and develop mouse diets with defined PC composition that we propose will lead to alterations in plasma LPA levels. The information in this aim will then be exploited to determine the impact of manipulations of dietary PC and pharmacological inhibition of the LPA generating enzyme autotaxin on breast cancer metastasis in mouse models. Completion of these studies will provide important new information about how a specific dietary constituent could contribute to breast cancer metastasis in humans and might also provide an impetus for future translational studies exploring the possibility that pharmacological inhibition of LPA synthesis and signaling could be a viable strategy to mitigate human breast cancer risk, particularly in obese subjects.