A calixpyrrole derivative acts as a GPER antagonist: mechanisms and models

Estrogens regulate numerous pathophysiological processes mainly binding to and activating the estrogen receptor (ER)α and ERβ. Increasing evidence has recently demonstrated that the G protein-coupled receptor 30 (GPR30/GPER) is also involved in diverse biological responses to estrogens in normal and cancer cells. The classical ER and GPER share several features, including the ability to bind to identical compounds, nevertheless some ligands exhibit opposed activity through these receptors. Worthy, the availability of selective agonists and antagonists of GPER has shown certain differential roles elicited by GPER respect to ER. Here, we provide evidence on the molecular mechanisms through which a calixpyrrole derivative acts as a GPER antagonist in different model systems, like breast tumor cells and cancer-associated fibroblasts (CAFs) obtained from breast cancer patients. Our data may open new perspectives toward the development of a further class of selective GPER ligands in order to better dissect the role exerted by this receptor in different pathophysiological conditions. Moreover, calixpyrrole derivatives may be considered in future anticancer strategies targeting GPER in cancer cells.