Steroid Receptors in Breast Cancer: Understanding of Molecular Function as a Basis for Effective Therapy Development

Abstract

Breast cancer remains one of the most important health problems worldwide. The family of steroid receptors (SRs), which comprise estrogen (ER), progesterone (PR), androgen (AR), glucocorticoid (GR) and mineralocorticoid (MR) receptors, along with a receptor for a secosteroid-vitamin D, play a crucial role in the pathogenesis of the disease. They function predominantly as nuclear receptors to regulate gene expression, however, their full spectrum of action reaches far beyond this basic mechanism. SRs are involved in a vast variety of interactions with other proteins, including extensive crosstalk with each other. How they affect the biology of a breast cell depends on such factors as post-translational modifications, expression of coregulators, or which SR isoform is predominantly synthesized in a given cellular context. Although ER has been successfully utilized as a breast cancer therapy target for years, research on therapeutic application of other SRs is still ongoing. Designing effective hormone therapies requires thorough understanding of the molecular function of the SRs. Over the past decades, huge amount of data was obtained in multiple studies exploring this field, therefore in this review we attempt to summarize the current knowledge in a comprehensive way.

Keywords: androgen receptor; breast cancer; estrogen receptor; glucocorticoid receptor; mineralocorticoid receptor; molecular function; progesterone receptor; steroid receptors; vitamin D receptor.

Figure 1

Structure and synthesis of ligands for SRs and VDR. Structures are shown only for steroids of highest affinity to their target receptor [4,6]. Since ERα and ERβ are encoded by different genes they are shown separately. Solid lines should be read as “is metabolized to” and dotted lines as “binds to”. Illustration created using elements from Servier Medical Art https://smart.servier.com/, reproduced under Creative Commons Attribution 3.0 Unported License https://creativecommons.org/licenses/by/3.0/.

Figure 2

Schematic illustration of steroid receptor structure. NTD—amino-terminal domain, DBD—DNA-binding domain, H—hinge region, LBD—ligand-binding domain, AF1—activation function 1, AF2—activation function 2. The diagram does not show the exact length proportion of the domains because it differs between distinct SRs.

Figure 3

SR synthesis, genomic signaling and degradation. (1) Translation of a SR and binding of Hsp70. (2) Hsp70 to Hsp90 transition. (3) Ligand binding, Hsp90 dissociation and dimerization. (4) Nuclear translocation. (5) Transcriptional action: induction (5a, 5c) or inhibition (5b, 5d) of target gene expression, performed either in the classical mechanism involving SRE-binding (5a, 5b) or by tethering other TFs (5c, 5d). (6) Ligand dissociation followed by disassembly of the transcriptional complex and SR binding to a molecular chaperone. (7) Rebinding of the ligand. (8) Ubiquitination. (9) Proteasomal degradation. SR—steroid receptor, SH—steroid hormone, Hsp 70—heat shock protein 70, Hsp90—heat shock protein 90, SRE—steroid response element, CoA—coactivators, CoR—corepressors, HAT—histone acetyltransferase, HDAC—histone deacetylase, TF—transcription factor, TFRE—transcription factor response element, Ub—ubiquitin. Although HATs and HDACs are classified as coregulators, here they are shown separately in order to emphasize their role. [2,16,17,31,32]. Illustration created using elements from Servier Medical Art https://smart.servier.com/, reproduced under Creative Commons Attribution 3.0 Unported License https://creativecommons.org/licenses/by/3.0/.