Choosing the right partner in hormone-dependent gene regulation: Glucocorticoid and progesterone receptors crosstalk in breast cancer cells

Abstract

Steroid hormone receptors (SHRs) belong to a large family of ligand-activated nuclear receptors that share certain characteristics and possess others that make them unique. It was thought for many years that the specificity of hormone response lay in the ligand. Although this may be true for pure agonists, the natural ligands as progesterone, corticosterone and cortisol present a broader effect by simultaneous activation of several SHRs. Moreover, SHRs share structural and functional characteristics that range from similarities between ligand-binding pockets to recognition of specific DNA sequences. These properties are clearly evident in progesterone (PR) and glucocorticoid receptors (GR); however, the biological responses triggered by each receptor in the presence of its ligand are different, and in some cases, even opposite. Thus, what confers the specificity of response to a given receptor is a long-standing topic of discussion that has not yet been unveiled. The levels of expression of each receptor, the differential interaction with coregulators, the chromatin accessibility as well as the DNA sequence of the target regions in the genome, are reliable sources of variability in hormone action that could explain the results obtained so far. Yet, to add further complexity to this scenario, it has been described that receptors can form heterocomplexes which can either compromise or potentiate the respective hormone-activated pathways with its possible impact on the pathological condition. In the present review, we summarized the state of the art of the functional cross-talk between PR and GR in breast cancer cells and we also discussed new paradigms of specificity in hormone action.

Keywords: chromatin; gene expression-regulation; glucocorticoid receptor; mammary epithelial cell proliferation; progesterone receptor.

Figure 1

(A) Domain structure of SHRs. i) Basic domain structure of SHRs is composed of an unstructured N-terminal domain (NTD) that contains the Activation Function 1 (AF-1) surface, a zinc finger DNA-binding domain (DBD), a flexible hinge region, and a LBD that binds to ligands and interacts with co-regulator proteins through the Activation Function 2 (AF-2) surface. ii) Domain size and amino acid length of different members of the SHRs sub-family. The DBD and LBDs are the most conserved regions whereas the other domains are more variable in length and sequence composition. (B) Mechanisms of action of SHRs. Individual action i) The canonical pathway is shown. Steroid hormone binding to the steroid hormone receptor (SHR), often in the cytoplasm, causes the receptor to undergo a conformational change and translocate to the nucleus, where it interacts with specific DNA sequences to regulate transcription of target genes. ii) Distribution of SHRs in liquid condensates or foci in the nucleus [Reviewed in (4)]. iii) Steroid hormone receptor could form multimers or quaternary structure after DNA binding (5, 6). Interesting, this mechanism brings together regions that may be distant in the linear genome. Crosstalk between SHRs. iv) The SHRs co-recruitment to DNA response elements occurs in presence of both ligands. As a result, this crosstalk triggers a specific gene program. SHRs= ERα/PR (7); SHRs= GR/PR (8); SHRs= ERα/GR (9). v) Redirection mechanism in which the presence of R5050 in GC-free medium leads to the binding of GR to REL and FHOX1 motifs and repress the expression genes required for PR function (8). On one hand, it has been described that R5020 can directly activate and could drive GR binding (10) but R5020 activated PR could also participate indirectly stabilizing REL and/or FOXH1, increasing GR binding. This possibility, although feasible, requires further investigation.