Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K.

Abstract

We have shown previously that the AKT2 pathway is essential for cell survival and important in malignant transformation. In this study, we demonstrate elevated kinase levels of AKT2 and phosphatidylinositol-3-OH kinase (PI3K) in 32 of 80 primary breast carcinomas. The majority of the cases with the activation are estrogen receptor alpha (ERalpha) positive, which prompted us to examine whether AKT2 regulates ERalpha activity. We found that constitutively activated AKT2 or AKT2 activated by epidermal growth factor or insulin-like growth factor-1 promotes the transcriptional activity of ERalpha. This effect occurred in the absence or presence of estrogen. Activated AKT2 phosphorylates ERalpha in vitro and in vivo, but it does not phosphorylate a mutant ERalpha in which ser-167 was replaced by Ala. The PI3K inhibitor, wortmannin, abolishes both the phosphorylation and transcriptional activity of ERalpha induced by AKT2. However, AKT2-induced ERalpha activity was not inhibited by tamoxifen but was completely abolished by ICI 164,384, implicating that AKT2-activated ERalpha contributes to tamoxifen resistance. Moreover, we found that ERalpha binds to the p85alpha regulatory subunit of PI3K in the absence or presence of estradiol in epithelial cells and subsequently activates PI3K/AKT2, suggesting ERalpha regulation of PI3K/AKT2 through a nontranscriptional and ligand-independent mechanism. These data indicate that regulation between the ERalpha and PI3K/AKT2 pathway (ERalpha-PI3K/AKT2-ERalpha) may play an important role in pathogenesis of human breast cancer and could contribute to ligand-independent breast cancer cell growth.

• Authors: M Sun, J E Paciga, R I Feldman, Z Yuan, D Coppola, Y Y Lu, S A Shelley, S V Nicosia, J Q Cheng
• Journal: Cancer research (Cancer Res) Vol. 61 Issue 16 Pg. 5985-91 (Aug 15 2001) ISSN: 0008-5472 [Print] United States
• PMID: 11507039 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Androstadienes
• Enzyme Inhibitors
• Estrogen Antagonists
• Estrogen Receptor alpha
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins
• Receptors, Estrogen
• Tamoxifen
• AKT2 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Wortmannin

Topics

• Androstadienes (pharmacology)
• Animals
• Breast Neoplasms (enzymology, genetics, metabolism)
• COS Cells
• Enzyme Activation
• Enzyme Induction
• Enzyme Inhibitors (pharmacology)
• Epithelial Cells (enzymology, metabolism)
• Estrogen Antagonists (pharmacology)
• Estrogen Receptor alpha
• Genes, Reporter
• Humans
• Phosphatidylinositol 3-Kinases (biosynthesis, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (biosynthesis, metabolism)
• Proto-Oncogene Proteins c-akt
• Receptors, Estrogen (antagonists & inhibitors, metabolism, physiology)
• Tamoxifen (pharmacology)
• Transcription, Genetic (physiology)
• Transfection
• Wortmannin