Progesterone Receptors in Prostate Cancer: Progesterone receptor B is the isoform associated with disease progression

Abstract

The role of steroid hormones in carcinogenesis of the prostate is to some extent unraveled thorough the effect of androgen deprivation therapy on prostate cancer (PCa) progression. Other members of the steroid hormone family, such as progesterone, are also implicated in PCa, but progesterone’s role remains undefined. This study aimed to examine the distribution of progesterone receptor isoforms (PGRA, PGRB) in PCa tissue and their association with clinical endpoints. This was conducted retrospectively by collecting radical prostatectomy specimens from 535 patients. Tissue was analyzed using tissue microarray, where representative tumor areas were carefully selected. Protein expression was evaluated through immunohistochemistry, in stromal and epithelial tissue. Associations between receptor expression and clinical data were considered using statistical survival analyses. Herein, we discovered a solely stromal PGRA- and a stromal and epithelial PGRB expression. Further, a high PGRB expression in tumor tissue was associated with an unfavorable prognosis in both univariate and multivariate analyses: Biochemical failure (HR: 2.0, 95% CI: 1.45–2.76, p < 0.001) and clinical failure (HR: 2.5, 95% CI: 1.29–4.85, p = 0.006). These findings are in agreement with our previous investigation on pan-PGR, indicating that the observed negative effect of PGR is represented by PGRB.

Chromatin accessibility analysis uncovers regulatory element landscape in prostate cancer progression

“…Here we were able to show that this AR, FOXA1, HOXB13 program is initially activated in PC then depleted during progression to CRPC, when it is substituted by the activation of alternative regulatory modules composed of several TFs previously reported to be important in progression to CRPC. These TFs include glucocorticoid receptor, known to have a role in developing resistance to antiandrogens (Arora et al, 2013), and progesterone receptor that has been associated with disease progression (Grindstad et al, 2015(Grindstad et al, , 2018. Overall, these analyses demonstrate that epigenetic chromatin reprogramming during CRPC progression enables binding sites for disease driving TFs, in addition to AR.…”

“…The second module contains a number of TFs with known function in driving aggressive prostate cancer e.g. glucocorticoid receptor (NR3C1) as well as TF coding genes MYC, HOXB13, GATA2, NKX3-1, and PGR (Chen et al, 2018;Grindstad et al, 2018;Isikbay et al, 2014;Koh et al, 2010;Rodriguez-Bravo et al, 2017). Surprisingly, genes targeted by this second module are a subset of AR module target genes ( Figure 4C).…”

Progesterone Receptor Expression in the Benign Prostatic Hyperplasia and Prostate Cancer Tissues, Relation with Transcription, Growth Factors, Hormone Reception and Components of the AKT/mTOR Signaling Pathway

“…Testosterone, dihydrotestosterone and androgen receptor (AR) plays a crucial role in the hormonal carcinogenesis (Quayle et al, 2007) However, researchers are increasingly attracted by PRs and their ligand -progesterone [4], which is a precursor to the synthesis of testosterone, cortisol. There are two progesterone receptor isoforms (PGRA, PGRB) in PCa tissue (Grindstad et al, 2015). It is believed that the level of PGRB expression is associated with a poor prognosis of Editorial Process: Submission:07/24/2019 Acceptance:02/11/2020 the disease and an inadequate response to ADT (Grindstad et al, 2018;Thomas et al, 2014).…”

“…There are two progesterone receptor isoforms (PGRA, PGRB) in PCa tissue (Grindstad et al, 2015). It is believed that the level of PGRB expression is associated with a poor prognosis of Editorial Process: Submission:07/24/2019 Acceptance:02/11/2020 the disease and an inadequate response to ADT (Grindstad et al, 2018;Thomas et al, 2014). The canonical pathway of progesterone activation occurs as follows: when PR is bound to its ligand, it penetrates the nucleus.…”

Progesterone: An Enigmatic Ligand for the Mineralocorticoid Receptor

“…Progesterone is considered to be a female reproductive steroid due to its regulation of gene expression in mammary gland and uterus, which affects many aspects of female reproductive physiology, including fertilization, maintenance of pregnancy and preparation of the endometrium for implantation and parturition [17][18][19][20]. However, progesterone also has important physiological actions in males including in prostate and testes [21][22][23][24]. Moreover, progesterone activates the PR in the brain, bone, thymus, lung and vasculature in females and males [25,26].…”