LAUSR

Abstract Macrophages are necessary in mammary gland development to drive ductal elongation and have been shown to promote cancer metastasis. Our laboratory has previously shown that macrophages are recruited to pre-invasive lesions to induce localized invasion during the switch from premalignant to invasive cancer. However, the mechanisms by which macrophages promote mammary gland development and early breast cancer progression are poorly understood. CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that regulates the growth and differentiation of myeloid and epithelial cells in various tissues. The goal of this study is to define the role of macrophage-C/EBPβ in mammopoiesis and early breast cancer progression. Conditional deletion of C/EBPβ in macrophages resulted in alterations in mammary branching and TEB formation, while ductal elongation remained normal. Interestingly, loss of C/EBPβ in macrophages using CSFR1-iCre mice induced an increase in eosinophils and overall F4/80+CD11b+, while lymphoid cells remained unchanged. Using a p53-null mouse model of premalignant progression (termed PN1a), we previously showed that macrophages are polarized by pre-invasive PN1a cells in vivo, and consequently induce a tumor-like phenotype. To determine whether C/EBPβ is required for macrophage polarization, macrophages were transduced with specific protein isoforms of C/EBPβ and various cytokines were examined. C/EBPβ-LAP2 induced an increase in TNFα and TGFβ expression, suggesting a distinct function for the individual isoforms. Polarizing Raw246.7 cells changes the expression of C/EBPβ indicating that the environment can effect C/EBPβ expression and cytokine production. Ongoing studies are aimed at delineating the consequences of C/EBPβ deletion in myeloid cells at different stages of breast cancer progression. The results of these studies will have critical implications for developing prevention strategies and for therapeutically targeting macrophages in early stage disease. These studies are supported by Susan G. Komen and NCI RO1 grants.