In our experimental approach, we co-cultured estrogen receptor (ER)-positive, poorly invasive and low metastasizing mammary cancer cells (MCF-7) or ER-negative, highly invasive and metastatic breast cancer cells (MDA-MB-231) with fibroblasts isolated from mammary healthy skin (NFs) or from breast tumor stroma (CAFs) in conventional 2D adherent cultures or in a 3D system (nodules). The gene discussed is ESR1; the disease is breast cancer.