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.
Being obese or overweight dramatically increases cancer risk, particularly in women, and obese or overweight cancer patients often experience worse clinical outcomes than normal weight individuals. However, the basis for this association of obesity with cancer risk and prognosis is not well understood. This proposal requests funds to support research training and career development for a promising underrepresented minority scientist who proposes to investigate a potential mechanism linking obesity to cancer risk and clinical outcomes.
