Estrogen Receptors Regulate Prostate Growth in Benign Prostatic Hyperplasia upon SRD5A2 Promoter Methylation
Christina Sharkey, BS, Sijun Liu, MD, Zongwei Wang, PhD, Aria F. Olumi, MD.
BIDMC, Boston, MA, USA.
Background: Steroid 5α-reductase type II (SRD5A2) is the predominant enzyme responsible for prostatic development and growth. We found that expression of SRD5A2 in the prostate is variable, and that one-third of prostate tissue samples from BPH patients do not express SRD5A2. We demonstrated that the absence of SRD5A2 expression is associated with SRD5A2 methylation in the promoter region. We have demonstrated that there is an “androgenic to estrogenic switch” when SRD5A2 is absent in the prostate gland. Here we wished to identify if SRD5A2 promoter methylation regulates estrogen receptor (ER) expression.Methods: We used human prostatic stromal and epithelium cells, and prostate specimens that collected from patients who underwent transurethral resection of the prostate (TURP). ERα and ERβ histological expression was determined by immunohistochemistry. Genome DNA was extracted and SRD5A2 promoter methylation was determined with DNA methylation-specific PCR. The level of SRD5A2 promoter methylation was correlated to ER expression.Results: ERβ was expressed in both stroma and epithelial compartments, whereas ERα was mainly expressed in the basal epithelium. In cultured prostatic stromal and epithelium cells, ERβ only expressed in the nucleus. Six out of twenty-three patients were SRD5A2 hypermethylation at the promoter region and had higher ERβ expression. Conclusions: ERα and ERβ co-localize in human benign prostatic tissue. Specifically, ERβ is expressed in the nucleus of both the prostatic stroma and epithelial. SRD5A2 promoter methylation is associated with the expression of ER. Targeting the estrogenic signaling may serve as an effective treatment strategy in subset of ER-sensitive BPH patients.
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