Article révisé par les pairs
| Résumé : | The evolution of breast cancers results from the emergence of epithelial cell subpopulations containing variant Estrogen Receptor α which is able to bypass conventional treatments aimed at antagonizing the activity of this tumor-promoting receptor. The present investigation concerns a few estradiol derivates bearing substituents in position 11β that might not only contribute to the development of drugs to alleviate this unfortunate issue but that may be also helpful in identifying molecular aspects of resistance to this receptor in order to elaborate other therapeutic approaches. In this regard, AP-1 assisted and ERE-directed ERα transcriptions are demonstrated to be key factors in this area: AP-1 transcriptions are shown to antagonize ERE transcriptions, thereby limiting their tumor-promoting activity. This property results from a conformal change in the receptor, which is induced essentially by estrogenic ligands which, inserted into a cavity of ERα’s ligand-binding pocket, govern this regulatory mechanism. Flexible 11β side-chains favor this insertion, in contrast to their rigid counterparts, which counteract it; these properties give rise to strong estrogenic, SERM or SERD profiles. Suspected extracellular regulatory mechanisms resulting from these ligand-induced transcriptions are elaborated on in the present work in the context of breast cancer development. |
