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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA180986-01A1
Application #
8749759
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Emenaker, Nancy J
Project Start
2014-09-01
Project End
2019-07-31
Budget Start
2014-09-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Organized Research Units
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Hao, Jiaqing; Yan, Fei; Zhang, Yuwen et al. (2018) Expression of Adipocyte/Macrophage Fatty Acid-Binding Protein in Tumor-Associated Macrophages Promotes Breast Cancer Progression. Cancer Res 78:2343-2355
Zeng, Jun; Zhang, Yuwen; Hao, Jiaqing et al. (2018) Stearic Acid Induces CD11c Expression in Proinflammatory Macrophages via Epidermal Fatty Acid Binding Protein. J Immunol 200:3407-3419
Yan, F; Shen, N; Pang, J X et al. (2018) A vicious loop of fatty acid-binding protein 4 and DNA methyltransferase 1 promotes acute myeloid leukemia and acts as a therapeutic target. Leukemia 32:865-873
Hao, Jiaqing; Zhang, Yuwen; Yan, Xiaofang et al. (2018) Circulating Adipose Fatty Acid Binding Protein Is a New Link Underlying Obesity-Associated Breast/Mammary Tumor Development. Cell Metab 28:689-705.e5
Zhang, Yuwen; Hao, Jiaqing; Zeng, Jun et al. (2018) Epidermal FABP Prevents Chemical-Induced Skin Tumorigenesis by Regulation of TPA-Induced IFN/p53/SOX2 Pathway in Keratinocytes. J Invest Dermatol 138:1925-1934
Yan, F; Shen, N; Pang, J X et al. (2017) Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells. Leukemia 31:1434-1442
Zhang, Yuwen; Hao, Jiaqing; Sun, Yanwen et al. (2017) Saturated Fatty Acids Induce Ceramide-associated Macrophage Cell Death. J Vis Exp :
Zhang, Yuwen; Rao, Enyu; Zeng, Jun et al. (2017) Adipose Fatty Acid Binding Protein Promotes Saturated Fatty Acid-Induced Macrophage Cell Death through Enhancing Ceramide Production. J Immunol 198:798-807
Rao, Enyu; Zhang, Yuwen; Li, Qiang et al. (2016) AMPK-dependent and independent effects of AICAR and compound C on T-cell responses. Oncotarget 7:33783-95
Li, Bing; Schmidt, Nathan W (2016) Epidermal Fatty Acid Binding Protein (E-FABP) Is Not Required for the Generation or Maintenance of Effector and Memory T Cells following Infection with Listeria monocytogenes. PLoS One 11:e0162427

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