Trophic effect in MCF-7 cells of ERα17p, a peptide corresponding to a platform regulatory motif of the estrogen receptor α -: Underlying mechanisms

As yet, estrogen receptor alpha (ER alpha) inhibitors used in clinical practice target a unique site, i.e. the hormone-binding pocket. With the aim of discovering other potential therapeutic targets in the receptor, we studied its AF-2a domain, a site that proves to be critical for ligand-independent ER alpha activity. Previous studies from our laboratory highlighted an auto-inhibitory action associated with a site included in this domain, i.e. the P-295-T-311 sequence. Accordingly, a deletion of this sequence produces a constitutively activated receptor mutant. More interestingly, a synthetic peptide with the P-295-T-311 sequence (ER alpha 17p) elicits in breast cancer cell lines estrogenic responses that may be ascribed to a competitive mechanism towards the P-295-T-311-associated auto-inhibition of ER(x. In the present study, we show that ER alpha 17p sustains MCF-7 cell growth in estrogen-depleted culture medium by inducing molecular events promoting G1/S phase transition. We demonstrate, moreover, that this proliferative activity is associated with receptor down regulation (acceleration of ER alpha degradation and repression of ESR1 gene transcription), similar to that induced by estrogen agonists. Complementary studies suggest that our observations may be, at least in part, relevant to a competitive inhibition affecting ER alpha-Hsp70 association. Hence, the design of drugs able to stabilize ER alpha-Hsp70 complexes - where the receptor is in an inactive conformation - may be of therapeutic value. (C) 2007 Elsevier Ltd. All rights reserved.