In conclusion, our data suggest that, by targeting IGFBP5 expression in ERα-positive breast cancer cells, such as MCF-7 cells, MSCs and CAFs are able to orchestrate a variety of events, particularly activation of the PI3K/AKT pathway, upregulation of Bcl-3 expression and desensitization to anti-estrogen. This evidence concerns the gene ESR1 and breast cancer.