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Epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and heregulin-β1 (HRG-β1), can modulate the expression and activity of the estrogen receptor-α (ER-α) via the phosphatidylinositol 3-kinase (PI 3-K)/Akt pathway in the ER-α-positive breast cancer cell line, MCF-7. Estradiol can also rapidly activate PI 3-K/Akt in these cells (nongenomic effect). The recent study examines whether Akt is involved in the ER-α regulation by estradiol (genomic effect). Stable transfection of parental MCF-7 cells with a dominant-negative Akt mutant, as well as the PI 3-K inhibitors wortmannin and LY 294,002, blocked the effect of estradiol on ER-α expression and activity by 70–80 and 55–63%, respectively. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of estradiol. The changes in ER-α expression and activity were abrogated in response to estradiol by an arginine to cysteine mutation in …