Studies proposed in this progress (submitted as a Program Project Grant) will test the effect of dietary energy restriction (DER) and/or the omega-3 fatty acid DHA on mammary carcinogenesis in an obesogenic rodent model and on breast cancer risk reduction in overweight and obese women. State-of-theart lipidomic analysis will identify the DHA metabolites responsible for the chemopreventive effect of DHA. This work is expected to lead to new prevention strategies effective against ER+ and ER- breast cancer and acceptable to women at risk because of the health promoting feature of our interventions.

Overall Program Goals and Specific Aims:

The Annual Report to the Nation on the Status of Cancer (1) clearly emphasizes the major contribution

of excess weight to the increased incidence of many cancers including breast cancer. The National Cancer

Institute does indeed recognize research aimed at addressing the obesity epidemic as one of its top priorities for reducing the cancer burden in the United States (RFA-CA-11-011). There is strong evidence that excess adiposity over the pre- and postmenopausal years increases the risk of postmenopausal breast cancer (2). The research proposed in this Program Project Grant (PPG) represents a novel approach in addressing this clinically important issue in a comprehensive and in-depth mechanistic fashion going from experiments in a translationally relevant obesogenic rodent model to a clinical intervention trial which closely mirrors the experimental approach employed in the preclinical studies. There are numerous novel aspects in the Aims proposed in this application. a) While the majority of evidence supporting a beneficial effect of dietary energy restriction (DER) has been obtained in experimental models of prevention of obesity, there is no information on the efficacy of DER in reducing breast cancer incidence when it is applied to already obese rats or humans, that is intentional weight loss (IWL). This is a significant gap of knowledge since 65% of the US population is either overweight or obese. This gap will be addressed by Project 2 where IWL via DER will be applied to an obesogenic rat model. These preclinical studies will be paralleled by the clinical trial proposed in Project 3 conducted in overweight and obese women where the effects of IWL on a validated tissue marker of breast cancer risk, e.g., breast density will be evaluated. b) Work done to a large extent in our laboratories suggests that the combination of IWL via DER and omega-3 fatty acids (n-3FA) may complement each other in their antitumor action. Although both interventions reduce proliferation and increase apoptosis in premalignant and malignant mammary epithelium, the predominant effect of IWL is on increasing apoptosis (3), whereas that of n-3FA is mainly on reducing proliferation (4). Therefore, we anticipate observing a superior anti tumor effect from the combination in the preclinical studies proposed in Project 2 and in the clinical trial in Project 3. c) Our preclinical studies testing the protective effect of fish oil against breast cancer (4, 5) suggest that the protective effect of fish oil is due to one of its components such as DHA. Importantly, using a lipidomic approach, the leader of Project 1 has identified several hydroxylated metabolites of DHA in fish oil fed rats with a superior antitumor action to that of the parent compound. Testing the chemopreventive effects of these compounds using novel liposomal formulations in ER+ and ER- preclinical models will be a major focus of interest of Project 1. d) The importance of metabolism of DHA in mediating its antitumor action will be further investigated by experiments proposed in Project 1 and Project 2 which will focus respectively on the LOX and CYP pathway, the third branch of the lipid metabolic cascade which has received limited attention. Project 1 will determine the impact of specific LOX inhibitors on the chemopreventive efficacy of DHA in both ER+ and ER- preclinical models. Project 2 will test the novel hypothesis that obesity diminishes the protective effect of DHA by reducing the level of CYP derived oxylipins which have recently been shown to have strong anti tumor action (6). DER would be expected, on the other hand, to potentiate the chemopreventive action of DHA by reversing the adverse effect of obesity on DHA metabolism through the CYP pathway. In sum, we anticipate that Project 1 and Project 2 will identify novel DHA metabolites produced either through the LOX (Project 1) or CYP pathway (Project 2) with potent antitumor action. The translational impact of these findings will be tested in Project 3 where the changes in plasma levels of these metabolites in response to DHA and/or DER will be assessed and correlated with parameters of antitumor activity. The Organic Synthesis/Analytical Chemistry Core will provide investigators of Projects 1 and 2 with uniform and quality controlled DHA metabolites. It will also quantify the levels of these compounds in biological samples from Project 1 and 2 and in the plasma samples from Project 3.

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