RESUMO
Macrophages have important roles in mammary gland development and tissue homeostasis, but the specific mechanisms that regulate macrophage function need further elucidation. We have identified C/EBPß as an important transcription factor expressed by multiple macrophage populations in the normal mammary gland. Mammary glands from mice with C/EBPß-deficient macrophages (Cebpb ΔM) show a significant decrease in alveolar budding during the diestrus stage of the reproductive cycle, whereas branching morphogenesis remains unchanged. Defects in alveolar budding were found to be the result of both systemic hormones and local macrophage-directed signals. RNA sequencing shows significant changes in PR-responsive genes and alterations in the Wnt landscape of mammary epithelial cells of Cebpb ΔM mice, which regulate stem cell expansion during diestrus. Cebpb ΔM macrophages demonstrate a shift from a pro-inflammatory to a tissue-reparative phenotype, and exhibit increased phagocytic capacity as compared to WT. Finally, Cebpb ΔM macrophages down-regulate Notch2 and Notch3, which normally promote stem cell expansion during alveolar budding. These results suggest that C/EBPß is an important macrophage factor that facilitates macrophage-epithelial crosstalk during a key stage of mammary gland tissue homeostasis.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT , Ciclo Estral , Macrófagos , Glândulas Mamárias Animais , Animais , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Feminino , Camundongos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Macrófagos/metabolismo , Ciclo Estral/genética , Camundongos Knockout , Receptores Notch/metabolismo , Receptores Notch/genética , Células Epiteliais/metabolismo , Fagocitose/genética , Camundongos Endogâmicos C57BL , Deleção de GenesRESUMO
Breast tumorigenesis relies on complex interactions between tumor cells and their surrounding microenvironment, orchestrated by tightly regulated transcriptional networks. C/EBPß is a key transcription factor that regulates the proliferation and differentiation of multiple cell types and modulates a variety of biological processes such as tissue homeostasis and the immune response. In addition, C/EBPß has well-established roles in mammary gland development, is overexpressed in breast cancer, and has tumor-promoting functions. In this review, we discuss context-specific roles of C/EBPß during breast tumorigenesis, isoform-specific gene regulation, and regulation of the tumor immune response. We present challenges in C/EBPß biology and discuss the importance of C/EBPß isoform-specific gene regulation in devising new therapeutic strategies.
