No abstract

In recent years, our knowledge on estrogen receptors (ER) has been modified profoundly with the identification and the deciphering of the role of its protein effectors, as well as with the deeper insight of its molecular structure/function dynamics, characteristics associated with its nucleo-cytoplasmic-membrane shuttling properties. Also, significant progress has been made concerning its turn-over and associated final proteasomal degradation processes.These advances could lead in the near future to the design and the synthesis of novel receptor-interacting drugs. Recently, a number of receptor-related peptides acting as specific ER ligands have been identified and extensively studied with respect to their estrogenic/antiestrogenic activities. Among them, ERa17p, a synthetic analog of the P 295 -T 311 sequence of ERa, has been shown to exert pseudo-estrogenic effects by interacting in the close vicinity of its hinge region (BF3 domain). Remarkably, this sequence appears as the epicenter of a number of post-transcriptional modifications as well as of the recruitment of co-regulators, suggesting that it would play a key role in ERa functions. Here, we provide evidence that ERa17p induces apoptosis in ERa-positive (MCF-7, T47D) and -negative (MDA-MB-231, SK-BR-3) breast cancer cells by an ERa-independent membrane mechanism, triggering major proapoptotic signaling cascades. Finally, ERa17p induces the regression of breast ERa-negative cancer tumor xenografts, without apparent toxicity, suggesting that it could represent a new attractive tool for the development of future promising therapeutic approaches, and providing a novel insight to ER regulation of cell fate.

ERα17p is a synthetic peptide corresponding to a regulatory motif located within the autonomous AF-2a region of the estrogen receptor α (ERα). ERα17p binds to the receptor and enhances its transcriptional activity. Structural characteristics of this peptide suggest that it interferes with intra-and/or interprotein interactions involving ERα.