PGR

The progesterone receptor (PR) encoded by the PGR gene, a nuclear hormone receptor that controls developmental processes as well as proliferation and differentiation during the reproductive cycle and pregnancy. PR also plays a role in the progression of endocrine-dependent breast cancer (PMID: 11256112). PR is a member of the nuclear/steroid hormone receptor (SHR) family of ligand-dependent transcription factors and is mainly expressed in female reproductive tissues and the central nervous system. After binding to its homologous steroid progesterone, PR regulates the expression of gene network and controls the development, differentiation and proliferation of target tissues, as well as the pathological process of endocrine cancer (PMID: 28651856, PMID: 22193050). PR is involved in several key signaling pathways and interactions with other proteins and transcription molecules (PMID: 23702927, PMID: 21803119, PMID: 24333793). PR is A modular protein, which consists of A C-terminal ligand binding domain (LBD), A central spherical DNA binding domain (DBD) and an amino terminal domain (NTD). Due to different promoters, there are two different subtypes of PR protein, namely PR-A truncated from the NTD domain and PR-B (PMID: 21803119). PR experiences a variety of post-translational modifications and has multiple phosphorylation sites, most of which are located in the NTD region. PR is phosphorylated when progesterone is deficient. In addition, CDK1/2, MAPK, PKA, DNA-PK and CK2 kinases can phosphorylate PR (PMID: 23838532, PMID: 10548881). PR can bind to specific progesterone response elements (PREs) on chromatin, which can recruit transcription coenzymes and related cofactors, thereby changing local chromatin structure, promoting transcriptional activation, and leading to activation or suppression of PR target genes (PMID: 20087430). PR can also change gene expression and affect related receptors and other transcription factors binding to DNA, including activator protein 1(AP-1), specific protein 1(Sp1), signal transduction and transcriptional activator 3 (Stat3), etc. (PMID: 15282324, PMID: 20876300, PMID: 18202149), and stable interactions between PR and chromatin are largely limited in the absence of progesterone ligands (PMID: 8388996). In addition to the regulation of transcription, PR also activates the signal transduction pathway of breast cancer cells through non-genomic mechanisms and is associated with immune escape (PMID: 17440047, PMID: 11545730, PMID: 28684637, PMID: 25479686). After binding to the hormone, PR is ubiquitinized in multiple ways and rapidly degraded by proteasome. This hormone-dependent receptor downregulation is closely related to transcriptional activation (PMID: 10655479). The expression of PR protein is associated with breast cancer, endometrial cancer and other cancers (PMID: 26881523, PMID: 28684637).

Anabolic steroids regulate progesterone receptors and can agonize or antagonize PR receptors, called selective progesterone receptor modulators (SPRMs), they were developed after the successful development of selective estrogen receptor modulators (SERMs), which antagonize the effect of estrogen on breast proliferation, even the proliferation of uterus (PMID: 15857972, PMID: 30661244). These include mifepristone, asoprisnil, telapristone acetate and vilaprisan et al (PMID: 28567743). SPRMs was first used to regulate progesterone, as an emergency contraceptive, and for the treatment of uterine fibroids, endometriosis and premenstrual syndrome (PMID: 29139105, PMID: 29274830, PMID: 18778186, PMID: 32031903). Mifepristone has weak binding affinity with androgen receptor (AR) and no affinity with ER or MR, but it can inhibit transcriptional activation of cells and has therapeutic effect on patients with uterine fibroids (PMID: 14698071, PMID: 8734008). Asoprisnil has a high affinity for PR and acts as a mixture of agonist and antagonist, but clinical development was discontinued in 2007 due to abnormal changes in endometrium (PMID: 17339234, PMID: 17356170). Ulipristal Acetate (UPA) has strong antagonism and partial excitability and is approved by THE FDA as a contraceptive, as well as for the preoperative and intermittent treatment of moderate to severe uterine fibroids (PMID: 14667994, PMID: 25542821). Telapristone Acetate (CDB-4124), originally developed as a contraceptive, showed no binding activity to ER in a breast cancer clinical trial, but had an effect on PR transcription (PMID: 27215412). Vilaprisan was first evaluated in 2017 and has strong selective binding activity against PR, low binding activity against AR and moderate to weak binding activity against GR. Compared to Mifepristone, Vilaprisan has strong PR antagonistic activity and is undergoing a large phase III clinical trial to study the efficacy and safety of oral treatment of uterine fibroids (PMID: 28185997, PMID: 23739217). Meanwhile, SPRMs has been used to study the adjuvant treatment of various reproductive system cancers, such as breast cancer, cervical cancer, endometrial cancer, ovarian cancer and prostate cancer, outside the reproductive system. For example, compared with monotherapy , Tamoxifen combined with Mifepristone produced more cell inhibition and cytotoxic activity in breast cancer cells (PMID: 17671693, PMID: 2720645), and can change the disease of ovarian cancer and improve the efficacy of cisplatin therapy for cervical cancer (PMID: 12390742, PMID: 10831354).