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 α (ERα) 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 ERα activity. Previous studies from our laboratory highlighted an auto-inhibitory action associated with a site included in this domain, i.e. the P295-T311 sequence. Accordingly, a deletion of this sequence produces a constitutively activated receptor mutant. More interestingly, a synthetic peptide with the P295-T311 sequence (ERα17p) elicits in breast cancer cell lines estrogenic responses that may be ascribed to a competitive mechanism towards the P295-T311-associated auto-inhibition of ERα. In the present study, we show that ERα17p 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 ERα 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 ERα–Hsp70 association. Hence, the design of drugs able to stabilize ERα–Hsp70 complexes – where the receptor is in an inactive conformation – may be of therapeutic value.