Non-genomic Action of Steroid Hormones: More Questions than Answers

In this chapter we aim to draw the attention of potential readers to several aspects of our research on non-genomic action of sex steroid hormones that have not as yet been fully investigated and might offer interesting developments in future studies. The first aspect concerns the dependence of phenotype on hormone concentration. The second, regards the analysis of mechanisms responsible for the simultaneous stimulation of cell migration and inhibition of proliferation. Besides its physiological relevance, the migration-proliferation dichotomy might also be involved in the intermediate stages of progression from hormone dependency to hormone independency in breast and prostate cancers. Thirdly, the increasing number of non-reproductive cells that respond to steroid hormones through receptor-mediated non-genomic action in the absence of receptor-dependent transcription challenges the classic model of steroid hormone action as restricted to classic cell types rather than valid for all steroid target cells. Cross talk between membrane receptors and nuclear steroid receptors regulates nuclear steroid receptor action. An additional cross talk occurring between membrane receptors and extra-nuclear steroid receptors modulates to a great extent the intensity of growth factor signaling. The observed convergence of steroid-stimulated steroid receptor heterodimers on signaling pathways enhances signaling and offers new flexibility in the use of steroid antagonists. Surprisingly, steroid receptor nuclear export is a crucial step in the proliferative response mediated by non-genomic action of steroid receptors. Finally, receptor association with signaling effectors and scaffold proteins is the key event that initiates non-genomic proliferative, anti-apoptotic and migratory programs. It is therefore a promising target for novel anti-cancer therapy. Each of these aspects has been analyzed in several cell types and in relation to different biological effects. Much more work is required to fully evaluate their role in hormone action and their application in cancer therapy.