Despite recent improvements in survival rates, breast cancer still kills nearly half-a-million women worldwide annually. As the two most predominant populations in breast cancer stroma, macrophages and adipocytes play central roles in breast tumorigenesis and progression. Thereby, modifications in these cells can greatly influence tumor behavior. The objectives of this proposal are to determine the role of adipocyte/macrophage fatty acid binding protein (A-FABP) in promoting breast cancer development through simultaneously targeting both macrophages and adipocytes and to develop inhibitors to modulate A-FABP activity for breast cancer therapy. A-FABP, abundantly expressed in macrophages and adipocytes, has been identified as a central regulator of metabolic and inflammatory pathways in these cells. Our preliminary studies demonstrate that A- FABP is significantly upregulated in human and murine breast/mammary cancers. In response to tumor stimulation, cytoplasmic A-FABP expression is markedly elevated in tumor associated macrophages (TAMs) whereas circulating A-FABP is mainly released by adipocytes. More importantly, A-FABP deficiency alters macrophage phenotype and protects mice against mammary tumor growth and metastasis. While obesity is associated with poor prognosis and increased mortality in patients with breast cancer, the mechanistic basis for this association remains unclear. We found that obesity increases A-FABP in both cytosol and the circulation, and promotes breast cancer progression. It is likely that A-FABP links obesity and breast cancer via regulating macrophage and adipocyte functions. Thus, we hypothesize that A-FABP, as an unidentified link underlying the obesity-breast cancer association, promotes the development of breast cancer through enhancing pro-tumor functions of macrophages and adipocytes. Therefore, modulating A-FABP activity will represent a novel strategy for breast cancer therapy.
Specific Aim 1 will answer how cytoplasmic A-FABP regulates macrophage functions for breast cancer progression. We hypothesize that upregulation of cytoplasmic A-FABP in TAMs reprograms the macrophages to promote a pro-tumor environment.
Specific Aim 2 will delineate how circulating A-FABP released by adipocytes contributes to breast cancer invasion. Experiments will designed to test the hypothesis that circulating A-FABP released by adipocytes favors breast cancer progression by inducing oncogenic signaling in tumor cells to increase their aggressiveness.
Specific Aim 3 will address whether obesity promotes breast cancer through increasing A-FABP expression. We propose that A-FABP represents an unidentified factor in obesity to promote breast cancer risk and inhibition of A-FABP with inhibitors may suppress breast cancer development and progression. In conclusion, the data collected will help us unravel the critical role of A-FABP in breast cancer development and identify specific A- FABP inhibitors for potential breast cancer therapy.
Breast cancer poses a major threaten to women's health. Uncovering new mechanisms of breast cancer development represents a critically important focus for breast cancer research. This proposal will establish A-FABP as a new player in breast cancer development. The data obtained will not only have basic science ramifications for understanding mechanisms of how A-FABP promotes breast tumorigenesis and progression, but will also have clinical impact for treatment of breast cancer.