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Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate

Selvaraj Muthusamy1, Stefan Andersson, Hyun-Jin Kim

  • 1Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA.

Proceedings of the National Academy of Sciences of the United States of America
|November 25, 2011
PubMed

Insights

Prostate growth is regulated by a balance between androgen receptor and estrogen receptor beta (ERβ) activation. The enzyme 17βHSD6 converts dihydrotestosterone (DHT) to 3β-Adiol, activating ERβ and inhibiting growth, a pathway lost in prostate cancer.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Urology

Background:

  • Prostate growth is influenced by androgen receptor (AR) and estrogen receptor beta (ERβ) signaling.
  • 5α-dihydrotestosterone (DHT) activates AR, promoting proliferation, while 5α-androstane-3β,17β-diol (3β-Adiol) activates ERβ, inhibiting it.
  • The balance between AR and ERβ activation dictates prostate growth.

Purpose of the Study:

  • To investigate the role of 17β-hydroxysteroid dehydrogenase type 6 (17βHSD6) in converting DHT to 3β-Adiol.
  • To determine if this conversion activates ERβ signaling in prostate cells.
  • To assess the expression of 17βHSD6 and ERβ in normal, hyperplastic, and cancerous prostate tissues.

Main Methods:

  • Cell-based assays using an estrogen response element-luciferase reporter system.
  • Expression of 17βHSD6 in living cells.
  • Immunohistochemical analysis of prostate tissues.

Main Results:

  • 17βHSD6 successfully converted DHT to 3β-Adiol in living cells, activating the ERβ reporter.
  • This conversion occurred at physiological DHT concentrations found in the prostate.
  • 17βHSD6 and ERβ were detected in benign prostatic hyperplasia and ERβ-positive cells but were absent in high-grade prostate cancers (Gleason grade > 3).

Conclusions:

  • 17βHSD6-mediated conversion of DHT to 3β-Adiol is a significant pathway for ERβ activation and prostate growth regulation.
  • This pathway is lost in advanced prostate cancer, suggesting a mechanism for uncontrolled proliferation.
  • Restoring this pathway could offer a therapeutic strategy for prostate cancer.

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