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.

Figure 1

Immunohistochemical staining for progesterone receptor A and B. Representative pictures of immunohistochemical staining for progesterone receptor A and B (PGRA and PGRB) expression in tissue microarray cores from prostate cancer prostatectomy specimens in addition to positive and negative control tissue. Microscope pictures taken with 15x magnification. PGRA panel: (A) low and (B) high stromal PGRA expression in a normal tissue core, (C) low and (D) intermediate - high stromal PGRA expression in a tumor tissue core, (E) negative tissue control in normal human brain tissue (F) positive tissue control in normal human endometrial tissue. PGRB panel: (A) low epithelial PGRB expression and low – intermediate stromal PGRB expression in a normal tissue core, (B) high epithelial PGRB expression and intermediate – high stromal PGRB expression in normal tissue core, (C) low – intermediate epithelial PGRB expression and low stromal PGRB expression in tumor tissue core, (D) high epithelial and stromal PGRB expression in a tumor tissue core, (E) negative tissue control in normal human brain tissue (F) positive tissue control in normal human endometrial tissue.

Figure 2

Kaplan-Meier curves presenting significant results from univariate analyses. The Kaplan-Meier curves demonstrate a high and low progesterone receptor B (PGRB) expression level dichotomized at mean value and the association with patient outcome. A reduction in biochemical failure free survival (BFFS) and clinical failure free survival (CFFS) was demonstrated for patients with a high expression of PGRB in both tumor epithelial cells (TE) (A,B) and tumor associated stromal cells (TS) (C,D). Significant p-value in bold (threshold p ≤ 0.05).