Impact of PKCδ on estrogen receptor localization and activity in breast cancer cells

Regulation of estrogen receptor (ER) function in breast cancer cells is a complex process involving different signalling mechanisms. One signal transduction component that appears to influence ER signalling is protein kinase C (PKC). PKC delta is a particular isoenzyme of the novel PKC subfamily that plays a role in growth control, differentiation and apoptosis. The aim of the present study was to investigate the impact of PKC delta on the regulation of the transcriptional activity of the human ER alpha. By using 12-O-tetradecanoylphorbol- 13-acetate (TPA), Bryostatin1 and Rottlerin, we show that active PKC delta is a proproliferative factor in estrogen-dependent breast cancer cells. Furthermore, activation of PKC delta by TPA resulted in activation and nuclear translocation of ER alpha and in an increase of ER-dependent reporter gene expression. Transfection and expression of the regulatory domain RD delta of PKC delta, which is inhibitory to PKC delta, inhibited the TPA-induced ER alpha activation and translocation. ER alpha was not phosphorylated by PKC delta; however, glycogen synthase kinase-3 (GSK3) was identified as a substrate of PKC delta. The expression of RD delta resulted in a decrease of TPA-induced GSK3 phosphorylation and translocation into the nucleus. We suggest that GSK3 plays a role in the PKC delta-related nuclear translocation of ER alpha.