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17beta-hydroxysteroid dehydrogenase type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition

Juliette A Aka1, Mausumi Mazumdar, Chang-Qing Chen

  • 1Research Center of the Laval University Hospital Center (CHUQ-CHUL) and Laval University, Québec, Canada.

Molecular Endocrinology (Baltimore, Md.)
|February 23, 2010
PubMed

Insights

Inhibiting 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) reduces breast cancer cell growth by increasing active androgen dihydrotestosterone (DHT) levels and decreasing estradiol (E2) synthesis. This dual action supports 17beta-HSD1 inhibition as a breast cancer therapy.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cancer Research

Background:

  • Estradiol (E2) stimulates breast cancer cell (BCC) growth, while dihydrotestosterone (DHT) exhibits antiproliferative effects.
  • 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) primarily synthesizes E2 but also inactivates DHT.
  • The precise roles of 17beta-HSD1 in sex hormone regulation and BCC proliferation require further elucidation.

Purpose of the Study:

  • To investigate the direct roles of 17beta-HSD1 in sex hormone metabolism and its impact on breast cancer cell proliferation.
  • To elucidate the mechanism by which 17beta-HSD1 influences estradiol and dihydrotestosterone levels in breast cancer cells.
  • To evaluate the therapeutic potential of 17beta-HSD1 inhibition in breast cancer treatment.

Main Methods:

  • Utilized RNA interference (gene knockdown) and a specific 17beta-HSD1 inhibitor in the T47D BCC line.
  • Determined DHT catabolism and concentration changes following 17beta-HSD1 inhibition or knockdown.
  • Performed crystal structure analysis of the 17beta-HSD1/DHT complex to understand binding modes.
  • Assessed the correlation between 17beta-HSD1 expression, hormone levels, and cell proliferation.
  • Measured the effect of 17beta-HSD1 inhibition on E2-induced pS2 gene expression.

Main Results:

  • 17beta-HSD1 inhibition suppressed DHT catabolism by 19%, while gene knockdown increased DHT concentration by 41%.
  • Crystal structure revealed DHT binds to 17beta-HSD1 in both normal and reverse modes, with a preference for the latter.
  • 17beta-HSD1 expression negatively correlated with DHT levels but positively correlated with E2 levels and BCC proliferation.
  • Inhibition of 17beta-HSD1 increased DHT's antiproliferative effect and enhanced E2-induced pS2 gene expression.

Conclusions:

  • 17beta-HSD1 promotes BCC growth through dual actions: enhancing estradiol synthesis and inactivating dihydrotestosterone.
  • 17beta-HSD1 inhibition increases DHT levels, augmenting its antiproliferative effect and potentially offering a therapeutic strategy.
  • Targeting 17beta-HSD1 may be a viable approach for breast cancer therapy, balancing estrogen modulation with DHT's beneficial effects.

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