This study demonstrates how the potentiating effects of E-2 on insulin signaling in endoplasmic reticulum-positive breast cancer cells are consequent to an enhanced IRS-1 expression. It induces an increase of both PI-3K/AKT and ERK1/2 activities. A direct action of E-2 in the regulating mouse IRS-1 gene is also investigated in both Chinese hamster ovary and MCF-7 cells that are transfected with mouse IRS-1 regulatory sequences. The authors have reported, for the first time, how E-2 induction of ERS-1 mRNA was correlated with a direct positive regulatory role Of E-2 on the IRS-1 promoter. This effect seems to be not strictly related to the cell type.