Low-Fat/Fish Oil Diet and prostate Cancer Outcomes in Human Cohorts and Mouse Mo

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Epidemiologic and preclinical studies support the role of a low fat diet and fish oil intake for the prevention and treatment of prostate cancer. A prospective pre-prostatectomy trial conducted by our group found that a low-fat diet with fish oil reduced proliferation in prostate cancer epithelium in radical prostatectomy specimens and we found that the RBC membrane omega-6/omega-3 (n-6/n-3) fatty acid ratio correlated with prostate tissue proliferation levels. Our collaborator, Dr. Olefsky, recently identified a G protein coupled receptor (GPR120) on macrophages that mediates the anti-inflammatory effects of EPA and DHA (omega-3 fatty acids in fish oil) and we identified GPR120 in prostate cancer stroma, in neutrophils, and macrophages. Based on these findings, we hypothesize that a low-fat diet with fish oil may confer its anti-inflammatory/anti-proliferative effects on prostate cancer through prostatic stromal GPR120 by modulating the tumor microenvironment. Based on our prior preclinical and clinical studies, we anticipate that a low-fat fish oil (LF/FO) diet will inhibit prostate cancer proliferation in men on active surveillance, that the RBC n-6/n-3 ratio will be a useful blood-based surrogate biomarker to monitor prostate cancer proliferation levels, and that subjects with higher GPR120 levels in prostate tissue will have greater antiproliferative effects in response to fish oil intake. Thus the Aims of our proposal are (1) To determine the contribution of GPR120 to prostate cancer proliferation in archived specimens (2) To determine if a LF/FO diet delays the development of prostate cancer, in part, through the GPR120 receptor by using PTEN and GPR120 knockout mouse models, and (3) to determine the efficacy a LF/FO intervention in men on active surveillance and identify potential surrogate biomarkers for prostate cancer proliferation. We will measure gene expression of GPR120 and related inflammatory pathways in laser captured stromal tissue from our previous clinical trial and correlate these findings with proliferation. A prospective trial will be conducted in 100 men on active surveillance randomized to a low-fat diet with fish oil supplements or to a control group and prostate biopsies will be analyzed for proliferation (Ki-67 index) and GPR120 receptor levels at baseline and 1-year.