Back to 2016 Annual Meeting
Methylation of 5-α reductase may trigger an androgenic to estrogenic switch in prostatic tissue growth
Keyan Salari, MD, PhD, Rongbin Ge, MD, PhD, Zongwei Wang, PhD, Seth K. Bechis, MD, Jian Hong, PhD, Aleksander Otsetov, MD, Chin-Lee Wu, MD, PhD, Shahin Tabatabaei, MD, Aria F. Olumi, MD.
Massachusetts General Hospital, Boston, MA, USA.
BACKGROUND: The steroid-5α reductase type 2 gene (SRD5A2) and protein play a significant role in the development and growth of prostate tissue. As a result, strategies to block SRD5A2 using 5-α reductase inhibitors remain a mainstay in the treatment of benign prostatic hyperplasia (BPH). Our previous studies show that 30% of adult prostates do not express the SRD5A2 gene or protein due to methylation of the promoter region of the SRD5A2 gene. We hypothesized that in the absence of prostatic SRD5A2 there may be alternate pathways driving growth of prostatic tissue. Here, we performed molecular profiling of prostatic tissue with and without SRD5A2 promoter methylation to determine whether molecular subtypes of clinical relevance could be identified.
METHODS: Prostatic tissue specimens were obtained from 22 patients with symptomatic BPH undergoing prostate debulking surgery. SRD5A2 promoter methylation status was determined by PCR. RNA was extracted from each specimen and whole-transcriptome profiling was performed using Illumina Human BeadChip Arrays. Supervised analysis of gene expression data was performed using Gene Set Enrichment Analysis (GSEA). Prostatic protein expression of SRD5A2, androgen receptor (AR), estrogen receptor (ER) subunits, and aromatase were determined in a panel of six BPH patients by Western blot, immunohistochemistry (IHC), and ELISA assays.
RESULTS: We performed whole-transcriptome profiling of prostatic tissue from 22 patients with symptomatic BPH. By GSEA, we compared the gene expression profiles of SRD5A2-methylated vs. unmethylated patients, and we found that estrogen response genes are among the most significantly upregulated genes in patients harboring SRD5A2 promoter methylation. To validate these results and define the relationship between androgen vs. estrogen signaling, we measured prostatic protein expression of SRD5A2, aromatase, and the androgen and estrogen receptors in a panel of six BPH patients with and without SRD5A2 methylation. We demonstrate that when SRD5A2 is absent, there are increased levels of aromatase and phosphorylated ERα (p-ERα). Aromatase enzyme levels were quantitated by ELISA and found to be significantly elevated in prostate samples lacking SRD5A2 expression.
CONCLUSIONS: Our study identifies for the first time that there are distinct molecular subtypes of BPH corresponding to the presence or absence of SRD5A2 methylation and protein expression, and we find that estrogen response genes are a key distinguishing feature of the two molecular subtypes. Our findings of elevated aromatase and p-ERα levels in samples lacking SRD5A2 expression suggests an “androgenic to estrogenic switch” that modulates prostatic growth. With this alternate growth pathway activated, targeting the aromatase-estrogen-ER axis may serve as an effective treatment strategy in carefully selected patients who lack SRD5A2 expression.
Back to 2016 Annual Meeting