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Selective inhibition of human 3β-hydroxysteroid dehydrogenase type 1 as a potential treatment for breast cancer

James L Thomas1, Kevin M Bucholtz, Balint Kacsoh

  • 1Division of Basic Medical Sciences, Mercer University School of Medicine, 1550 College St, Macon, GA 31207, USA. Thomas J@mercer.edu

The Journal of Steroid Biochemistry and Molecular Biology
|August 26, 2010
PubMed

Insights

Human 3β-hydroxysteroid dehydrogenase/isomerase type 1 (3β-HSD1) is a key enzyme in breast tumor growth. Inhibitors like trilostane show higher affinity for 3β-HSD1, suggesting it

Area of Science:

  • Biochemistry
  • Enzyme kinetics
  • Molecular biology

Background:

  • Human 3β-hydroxysteroid dehydrogenase/isomerase type 1 (3β-HSD1) is crucial for converting DHEA to estradiol in breast tumors.
  • 3β-HSD1 inhibition is a potential therapeutic strategy for breast cancer in postmenopausal women.
  • Human 3β-HSD2 is involved in cortisol and aldosterone production in the adrenal gland.

Purpose of the Study:

  • To investigate the differential inhibition of human 3β-HSD1 and 3β-HSD2 by trilostane and epostane.
  • To elucidate the structural basis for the selective inhibition of 3β-HSD1.

Main Methods:

  • Recombinant expression of 3β-HSD1 and 3β-HSD2 in MCF-7 cells.
  • Enzyme inhibition assays (IC50 and Ki determination).
  • Site-directed mutagenesis and kinetic analysis.
  • Molecular docking and structural modeling.

Main Results:

  • Trilostane and epostane exhibited 12-16 fold lower IC50 values against 3β-HSD1 compared to 3β-HSD2.
  • Competitive inhibition of 3β-HSD1 by trilostane, contrasted with non-competitive inhibition of 3β-HSD2.
  • Arg195 in 3β-HSD1 and His156 in 3β-HSD1 were identified as critical residues for selective inhibitor binding.
  • Mutagenesis studies confirmed the role of Arg195 and His156 in differential enzyme inhibition.

Conclusions:

  • The differential inhibition of 3β-HSD1 and 3β-HSD2 by trilostane and epostane is attributed to specific amino acid residues (Arg195, His156) and subunit interactions.
  • These findings support the development of targeted inhibitors of 3β-HSD1 for breast cancer therapy.

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