Steroid receptor coactivators as therapeutic targets in the female reproductive system

Abstract

The Steroid Receptor Coactivators (SRCs/p160/NCOA) are a family of three transcriptional coregulators initially discovered to transactivate the transcriptional potency of steroid hormone receptors. Even though SRCs were also found to modulate the activity of multiple other transcription factors, their function is still strongly associated with regulation of steroid hormone action and many studies have found that they are critical for the regulation of reproductive biology. In the case of the female reproductive tract, SRCs have been found to play crucial roles in its physiology, ranging from ovulation, implantation, to parturition. Not surprisingly, SRCs’ action has been linked to numerous abnormalities and debilitating disorders of female reproductive tissues, including infertility, cancer, and endometriosis. Many of these pathologies are still in critical need of therapeutic intervention and “proof-of-principle” studies have found that SRCs are excellent targets in pathological states. Therefore, small molecule modulators of SRCs’ activity could be applied in the future in the treatment of many diseases of the female reproductive system.

Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

“…In general, nuclear receptor coregulators form large complexes to modify chromatin structure and regulate large-scale gene transcription programs [104]. A family of regulatory proteins aptly named steroid receptor coactivators (SRCs), composed of SRC-1, SRC-2, and SRC-3, is critical to the regulation of PGR and ESR1 action in the female reproductive tract [105]. In the endometrium, SRC-1 and SRC-2 appear to be the most functionally relevant for normal functionality based on studies utilizing knockout mice [106,107,108,109,110,111].…”

Estrogen Signaling in Endometrial Cancer: a Key Oncogenic Pathway with Several Open Questions

“…Studies into endometrial cancer-specific transcription factors and cofactors are sure to uncover interesting biology and shed light on how cell type-specific gene regulation through ER occurs. The discovery of endometrial cancer-specific ER influencing transcription factors and ER binding cofactors may also uncover clinical vulnerabilities that could be exploited in the treatment of endometrial cancer [ 137 ].…”

Steroid hormone receptors and prostate cancer: role of structural dynamics in therapeutic targeting

“…The AR is an important therapeutic target in prostate cancers, and the “Holy Grail” for AR as therapeutic targets is the potential to confine their actions by small-molecule ligands/hormones to specific cell/tissue types and gene targets 21. Binding of agonistic or antagonistic ligands leads to different allosteric changes in AR, allowing them to exert positive or negative effects on the expression of target genes in a differential manner depending on the physiological and genetic context of the cell 222324252627. The most widely used small-molecule ligands target the ligand binding pocket and exhibit varying degrees of agonist or antagonist activities associated AF2 orientation 28…”