The Epithelial mesenchimal transition (EMT) program depends on a series of intracellular signaling networks involving, among others signal-transduction proteins, ERK, MAPK, PI3K, and c-Fos.

Induction of c-Fos expression in normal mouse mammary epithelial cells induces EMT and is associated with a decrease in E-cadherin expression. Previous to EMT, CD44high/CD24high cells correspond to the phenotype of the majority of cells found in breast carcinomas whereas a shift to CD44+/CD24- cells, promotes EMT and a profile associated with human breast cancer stem cells (CSC) leading to the acquisition of mesenchymal qualities and an increased ability to form mammospheres and increased metastatic potential. We found, that the microenvironment formed by

macrophages induces both EMT in breast cancer cells with a stem cell?like phenotype and overexpression of c-Fos. Additionally, in cultures, this microenvironment induces proliferation, invasiveness, and migration of these breast cancer cells, even in presence of Tamoxifen. Macrophages-Breast Cancer Cells cocultured induced a sustained release of IL-6 from both cell types, leading to activation of ERK, STAT3 and c-Fos in the breast cells and also Tamoxifen resistance. Furthermore, this microenvironment increases breast tumor growth when macrophages are co-injected with MCF-7 cells into immunocompromised mice and Tamoxifen resistance.