Intestinal phosphatidylcholine exposure and breast cancer risk

 描述（由申请人提供）：饮食依赖性肥胖是许多癌症（包括绝经后乳腺癌）的危险因素。肥胖还与乳腺癌患者中更具侵袭性的乳腺癌亚型和较差的临床结局相关。绝经后乳腺癌患者超重和肥胖的患病率不断增加，因此确定肥胖与乳腺癌风险和预后之间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，或确定乳腺癌风险评估的标志物或药物干预的目标，以减轻与肥胖相关的乳腺癌风险。这个K 01应用程序的目的是支持在先进的质谱/代谢组学和临床前模型，这将使我成为一个独立的研究者在肥胖和癌症研究的接口工作的指导培训。解释肥胖和癌症风险之间联系的一个广泛假设是，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质或脂质衍生分子的产生有关，这些脂质或脂质衍生分子本身促进疾病。我建议调查的可能性，肠暴露于磷脂酰胆碱（PC）构成的饮食和乳腺癌风险之间的联系，通过促进PC衍生的生物活性脂质，溶血磷脂酸（LPA）的合成。乳腺癌细胞对LPA有强烈的反应，LPA刺激它们在体外的迁移、生长和存活。LPA合成和信号传导的遗传和药理学靶向减弱小鼠模型中的乳腺癌肿瘤生长和转移。我们提出，饮食消费富含PC的食物或PC分泌到胃中作为胆汁响应于脂肪餐导致这种脂质作为其溶血衍生物lysoPC（LPC）的摄取，lysoPC（LPC）作为来源于母体的脂蛋白的组分在血液中转运，其中其作为通过分泌的溶血磷脂酶D（autotaxin）产生LPA的底物。为了支持这一观点，我们表明小鼠和人类的血浆LPA水平对禁食和再喂养非常敏感，并且在小鼠中，饮食PC可以在血液中转化为LPA。为了解决我们的假设，我们将使用质谱法来监测小鼠中膳食PC的代谢，并开发具有我们提出的将导致血浆LPA水平改变的限定PC组成的小鼠膳食。然后，将利用这一目标中的信息来确定在小鼠模型中操作膳食PC和药理学抑制LPA生成酶自分泌运动因子对乳腺癌转移的影响。这些研究的完成将提供关于特定饮食成分如何有助于人类乳腺癌转移的重要新信息，也可能为未来的转化研究提供动力，探索LPA合成和信号传导的药理学抑制可能是减轻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.