Pentagalloylglucose inhibits estrogen receptor α by lysosome-dependent depletion and modulates ErbB/PI3K/Akt pathway in human breast cancer MCF-7 cells

Estrogens and estrogen receptors (ER) play important roles in estrogen-dependent and ER-positive breast cancer development. Inhibitors against estrogen biosynthesis or anti-estrogens have been used in breast cancer treatment for many years. The aim of this study was to determine whether pentagalloylglucose (5GC) has inhibitory effects on ER function. In the present study, we found that 5GG significantly reduced the growth of estrogen-responsive human breast cancer MCF-7 cells, and suppressed the phosphorylation and protein level of estrogen receptor alpha (ER alpha). Interestingly, 5GG decreased ER alpha protein levels by promoting the degradation of ERa protein in the lysosome. The ERa can be activated through a ligand-dependent and/or a ligand-independent pathway. The activated Akt kinase was shown to directly phosphorylate ER alpha at its serine residues and cause ligand independent activation. Our results showed that 5GG might inhibit the phosphatidylinositol 3-kinase(PI3K)/Akt pathway either through directly inhibiting Akt kinase actlvity or through inhibiting phosphorylation of the upstream receptor tyrosine kinases. The depletion of ErbB family receptors, including epidermal growth factor receptor (EGFR), ErbB2, and ErbB3, was also observed. 5GG treatment also led to a dose-dependent decrease in the expression of the estrogen-activated cyclin D1 expression. These findings suggested that 5GG might be a useful chemopreventive or therapeutic agent for hormone-dependent breast cancer through suppressing the functions of Hot by lysosome-dependent depletion and modulating the ErbB/PI3K/Akt pathway. (c) 2006 Wiley-Liss, Inc.