Steroid hormone receptors: A South American perspective

PATRICIA V ELIZALDE; CECILIA J PROIETTI

STEROIDS

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2020 vol. 155

0039-128X

The current special issue includes six reviews from several groups inSouth America which encompass the state-of-the-art research in thenuclear receptor arena. The nuclear receptor (NR) superfamily iscomposed of a group of transcription factors that act in cell type- andgene specific manners to regulate numerous physiological and pathologicalprocesses including carbohydrate and lipid metabolism, reproduction,inflammation, cancer, and cardiovascular disease [1]. Ourknowledge of the NR family has drastically expanded within the lastdecade due to advancements in genome‐wide methodologies, structuralstudies of receptor domains and full‐length complexes, and identificationof new co‐regulator proteins that modulate receptor activity [2].NRs are divided into seven subfamilies [3], and include the group of thesteroid receptors (SRs), which comprises the mineralocorticoid receptor(MR), androgen receptor (AR), estrogen receptor (ER), progesteronereceptor (PR), and glucocorticoid receptor (GR). SRs rapidly shuttlebetween the cytoplasm and the nucleus in both the absence and thepresence of hormone ligands. Unliganded SRs are typically bound inmultiprotein cytoplasmic complexes containing heat-shock protein(HSP) chaperone molecules. Upon ligand binding, receptors undergo aconformational change, resulting in dissociation of HSP-containingcomplexes and greater SR retention in the nucleus. Liganded SRs bindhormone response elements (HREs) in chromatin as dimers that activateor repress transcription of target genes via recruitment of coactivatorsor corepressors. In addition to directly binding DNA elements,SRs regulate gene expression via tethering to other transcription factors[4]. Moreover, SRs often regulate target genes via tethering and/ordirect binding to HRE enhancer elements located great distances (i.e.kilobases) from the transcriptional start sites of the genes they repressor activate [5]. Together with their direct transcriptional effects, SRactivate signal transduction pathways through a rapid or nongenomicmechanism [6,7], which may be regulated by post-translational modifications(PTMs) of the SR. Said PTMs include phosphorylation, acetylation,ubiquitination and SUMOylation. Specific PTMs have also beendescribed incertain SRs (methylation for PR, ER and AR; oxidation forGR and MR; and nitrosylation for GR), and have been reviewed in[8?11]. PTMs are clearly important contributing mechanisms to thediversity and context-dependent functions of SR and are involved in thecrosstalks between steroid hormone and growth factor signaling pathways.Latin American scientists have made important contributions to thefield of nuclear receptor research. The Argentinean Bernardo Houssay isone of the major contributors and first Nobel laureate in sciences in theregion due to his discoveries on the role of the anterior hypophysisgland in carbohydrate metabolism. Indeed, Houssay inferred that carbohydratemetabolism did not depend merely on the action of insulinalone, but also on the feedback and interplay of insulin and additionalhormones produced in the anterior pituitary. We now know that growthhormone is the critical hormone involved. Houssay?s discovery wasmonumental in establishing a more precise understanding of carbohydratemetabolism and the pathophysiology of diabetes mellitus. Mostimportantly, this work was catalytic in shifting general endocrine researchtoward the unravelling of hormonal feedback loops, which arecentral to all aspects of modern endocrinology and hormone-receptorinteraction [12].Cenciarini and Proietti specifically address the molecular mechanismsof progesterone/PR actions that drive epithelial cell proliferationand the regulation of the stem cell population in the normal breast andin breast cancer. Both the mechanisms for PR-dependent transcriptionalactivation and repression are outlined. Of particular interest is theoverview on the latter mechanism: the authors describe three differentmechanisms reported for PR transcriptional repression. The participationof PR/progesterone in breast cancer is examined considering theevidence provided by epidemiological studies and research conductedin animal models. Further features of PR mechanisms of action in breasttumors which contribute to tumorigenesis are discussed, like switch oftumor cells to an autocrine regulation of cell proliferation, extensivecrosstalk with Erbb2, interplay between PR and ER, the existence of analtered PR-A/PR-B ratio, and the regulation of the breast cancer stemcell population.Figueroa and coworkers provide a timely review about the interplaybetween SRs and the fibroblast growth factors/fibroblast growth factorreceptor (FGF/FGFR) pathways. Both the canonical membrane-activatedFGF/FGFR and the non-canonical nuclear-activated FGF/FGFRpathways are described in detail. Special emphasis is posed on thenuclear action of FGF members in ovarian, prostate and breast cancer,highlighting their involvement in endocrine resistance. The authorspropose the combined treatment of FGFR inhibitors with other drugtargets to enhance or restore endocrine sensitivity in hormone receptorpositive tumors.Camilletti et al. illustrate the controversy surrounding the physiologicaleffects of progesterone on the regulation of the pituitary gland.In particular, they describe progesterone actions in the secretion of thehormone prolactin and in the development of benign prolactin-secretingadenomas. They point out that the discovery of the membranetype of PR (mPR) shed light on the existing results and revolutionizedthe role of progesterone in prolactin regulation. In addition, mPRs arepositioned as likely candidates for the treatment of pathological hyperprolactinemia,given their pivotal involvement in the hypothalamicpituitaryaxis.Ortiz and coworkers present a clinical case of a TSH-secreting pituitaryadenoma responsive to somatostatin analogs. Although steroidreceptors are not specifically involved, this review poses special interestdue to the particular condition of the case reported, since 36% of thesetumors secrete ACTH while others are plurihormonal.