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

Biochem Biophys Res Commun. 2005 Nov 4;336(4):1221-6. doi: 10.1016/j.bbrc.2005.08.256.


Estrogen stimulates cell proliferation in breast cancer. The biological effects of estrogen are mediated through two intracellular receptors, estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta). 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 (PIP(3)), which is generated from phosphatidylinositol 4,5-bisphosphate via PI3K activation. The present study demonstrates that 17beta-estradiol (E2) up-regulates PI3K in an ERalpha-dependent manner, but not ERbeta, and stimulates cell growth in breast cancer cells. In order to study this phenomenon, we have treated ERalpha-positive MCF-7 cells and ERalpha-negative MDA-MB-231 cells with 10nM 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 PIP(3) 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 ERalpha-dependent. These results suggest that estrogen activates PI3K/Akt signaling through ERalpha-dependent mechanism in MCF-7 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Estradiol / pharmacology
  • Estradiol / physiology*
  • Estrogen Receptor alpha / agonists*
  • Estrogen Receptor beta / agonists*
  • Female
  • Humans
  • Mammary Glands, Human / metabolism
  • Mammary Glands, Human / pathology
  • Phosphatidylinositol 3-Kinases / biosynthesis
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / biosynthesis
  • Proto-Oncogene Proteins c-akt / physiology*
  • Signal Transduction
  • Up-Regulation


  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 3,4,5-triphosphate
  • Estradiol
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt