The increasing incidence of breast cancer poses a major threat to women's health in the USA and worldwide. How to prevent breast tumorigenesis and to identify new protective factors for the control of breast cancer represents a great challenge in this field. The objectives of this proposal are to unravel a protective role of epidermal fatty acid binding protein (E-FABP) in preventing breast cancer development and to determine the molecular mechanisms by which E-FABP regulates IFNb production and signaling in a specific subset of tumor associated macrophages for antitumor responses. E-FABP, abundantly expressed in macrophages, has been recognized as an important regulator to coordinate cell metabolic and inflammatory pathways. Our preliminary studies demonstrate that E-FABP deficient mice exhibit significant increases in mammary tumor growth and lung metastasis compared to wild type mice, suggesting a protective role of host expression of E-FABP in mammary tumor prevention. Further analysis of E-FABP expression profile indicates that E-FABP is specifically expressed in the subset of F4/80+CD11b+MHCII+CD11c+ cells. Microarray and qPCR experiments show that tumor-induced IFN? production and signaling in macrophages are significantly impaired by E-FABP deficiency. Interestingly, IFNb stimulation specifically induces E-FABP upregulation in the process of M1 polarization. Moreover, o-3 fatty acids can greatly enhance E-FABP expression in macrophages. Thus, we hypothesize that E-FABP may regulate macrophage function by promoting IFNb production, signaling and M1-like phenotype switch through enhancing cell lipid metabolism. E-FABP, as a new cancer protective factor, can prevent breast carcinogenesis through promoting macrophage anti-tumor responses. Therefore, modulating E-FABP activity will represent a novel strategy for breast cancer prevention.
Specific Aim 1 will determine how E-FABP regulates IFNb production in macrophages. We hypothesize that E-FABP is an unidentified host-derived factor to regulate tumor-induced IFNb production through impacting lipid-mediated signals in specific subsets of macrophages.
Specific Aim 2 will determine how E-FABP regulates IFNb signaling to promote anti-tumor responses. We will test the hypothesis that E-FABP-regulated IFNb signaling promotes tumor specific T lymphocyte infiltration and IFNb production, which further upregulates E-FABP expression to facilitate macrophage M1 polarization for antitumor immunity.
Specific Aim 3 will address whether host-derived E-FABP protects against breast cancer development in clinically relevant animal models and in humans. We will verify E-FABP as a host-derived protective factor in breast cancer prevention and establish an effective strategy for the control o breast cancer via dietary upregulation of E-FABP. In conclusion, successful completion of this project will reveal E-FABP as a new protective factor in control of breast cancer development and help us develop an effective strategy to prevent breast cancer via targeting E- FABP.
Breast cancer poses a major threat to women's health. Identifying new protective factors and uncovering the molecular mechanisms of their action represent critically important foci for the control of breast cancer. This proposal will establish -FABP as a new protective factor for breast cancer prevention. The data obtained will not only have basic science ramifications for understanding mechanisms of how E-FABP prevents breast tumorigenesis and progression, but will also have clinical impact for the prevention of breast carcinogenesis.