Fig. 7

MenaINV expression in cancer cells is induced by macrophage-mediated cooperative NF-κB and Notch1 signaling. Juxtacrine and paracrine signaling between macrophages and tumor cells activate Notch1 and NF-κB pathways which cooperate to induce MenaINV expression in cancer cells. A Notch1 signaling alone does not induce MenaINV expression in tumor cells. B NF-κB signaling, activated by TNFα binding to the TNFR1 receptor, causes nuclear translocation of the transcription factor p65 and a 1.5-fold increase in MenaINV expression. C Notch1 and NF-κB signaling crosstalk to increase MenaINV expression further to 2.5-fold. Notch1 intracellular domain (NICD) enhances nuclear retention of NF-κB transcription factor p65 leading to sustained NF-κB signaling and induction of MenaINV expression. This mechanism of MenaINV induction is present in vivo and it explains previously observed increase in MenaINV expression upon in chemotherapy treatment [19]. This detailed understanding of MenaINV induction in clinically relevant scenarios is needed for future development of combination therapies to improve survival of patients with breast cancer. Figure created with BioRender.com