Up-regulation of PI3K/Akt signaling by 17β-estradiol through activation of estrogen receptor-α but not estrogen receptor-β, and stimulates cell growth in breast cancer cells

Estrogen stimulates cell proliferation in breast cancer. The biological effects of estrogen are mediated through two intracellular receptors, estrogen receptor-alpha (ER alpha) and estrogen receptor-beta (ER beta). However, the role of ERs in the proliferative action of estrogen is not well established. Recently, it has been known that ER activates phosphatidylinositol-3-OH kinase (PI3K) through binding with the p85 regulatory subunit of PI3K. Therefore, possible mechanisms may include ER-mediated phosphoinositide metabolism with subsequent formation of phosphatidylinositol-3,4,5.-trisphosphate (PIP3) which is generated from phosphatidylinositol 4,5-bisphosphate via PI3K activation. The present study demonstrates that 17 beta-estradiol (E2) up-regulates PI3K in an ER alpha-dependent manner, but not ER beta, and stimulates cell growth in breast cancer cells. In order to study this phenomenon, we have treated ER alpha-positive MCF-7 cells and ER alpha-negative MDA-MB-231 cells with 10 nM E2. Treatment of MCF-7 cells with E2 resulted in a marked increase in PI3K (p85) expression, which paralleled an increase in phospho-Akt (Ser-473) and PIP3 level. These observations also correlated with an increased activity to E2-induced cell proliferation. However, these effects of E2 on breast cancer cells were not observed in the MDA-MB-231 cell line, indicating that the E2-mediated up-regulation of PI3K/Akt pathway is ER alpha-dependent. These results suggest that estrogen activates PI3K/Akt signaling through ER alpha-dependent mechanism in MCF-7 cells. (c) 2005 Elsevier Inc. All rights reserved.