Tumor phenotype is a result of the complex interactions between malignant cells and sorrounding stroma. However, the mechanisms by which cancer cells and fibroblasts, the most abundant and active part of the tumor stroma, interact remain to be elucidated. The K303R mutation of estrogen-receptor (ERα) was identified in 50% of invasive breast tumors and associated with poorer survival outcomes. Here, we show that human cancer-associated fibroblasts (CAFs) stimulated proliferation and migration of wild-type (WT) ERα stably transfected breast cancer cells and to a higher extent in cells expressing the K303R ERα hyperactive receptor. We identified, for the first time, leptin, a known cytokine involved in breast cancer development, as a determinant for CAFs tumor-promoting activities in both WT and K303R ERα-expressing cells. Indeed, we found an increase in leptin receptor isoforms expression, and in its signalling activation in K303R-expressing cells compared to WT ERα clones. These data correlated well with the amplified effects of leptin on cell growth, motility and invasiveness in mutant cells. Mutant expression generated a leptin hypersensitive phenotype also in vivo. Lastly, K303R ERα cell-secreted factors stimulated CAFs proliferation and migration and their ability to secrete leptin. We demonstrated that the epidermal growth factor is the paracrine factor by which breast cancer cells affect CAFs phenotype. Thus, our work uncovers a bidirectional cross-talk between breast cancer cells and ‘educated’ CAFs, which leads via leptin signaling to increased tumor progression. The blockade of these intercellular communications might represent an effective strategy for molecular targeted therapies in breast cancer.