Selective inhibition of human 3β-hydroxysteroid dehydrogenase type 1 as a potential treatment for breast cancer
Open accessAbstract
Human 3β-hydroxysteroid dehydrogenase/isomerase type 1 (3β-HSD1) is a critical enzyme in the conversion of DHEA to estradiol in breast tumors and may be a target enzyme for inhibition in the treatment of breast cancer in postmenopausal women. Human 3β-HSD2 participates in the production of cortisol and aldosterone in the human adrenal gland in this population. In our recombinant human breast tumor MCF-7 Tet-off cells that express either 3β-HSD1 or 3β-HSD2, trilostane and epostane inhibit the DHEA-induced proliferation of MCF-7 3β-HSD1 cells with 12-16-fold lower IC(50) values compared to the MCF-7 3β-HSD2 cells. Trilostane and epostane also competitively inhibit purified human 3β-HSD1 with 12-16-fold lower K(i) values compared to the noncompetitive K(i) values measured for human 3β-HSD2. Using our structural model of 3β-HSD1, trilostane was docked in the active site of 3β-HSD1, and Arg195 in 3β-HSD1 or Pro195 in 3β-HSD2 was identified as a potentially critical residue. The R195P-1 mutant of 3β-HSD1 and the P195R-2 mutant of 3β-HSD2 were created, expressed and purified. Kinetic analyses of enzyme inhibition suggest that the high-affinity, competitive inhibition of 3β-HSD1 by trilostane may be related to the presence of Arg195 in 3β-HSD1 versus Pro195 in 3β-HSD2. In addition, His156 in 3β-HSD1 may play a role in the higher affinity of 3β-HSD1 for substrates and inhibitors compared to 3β-HSD2 containing Try156. Structural modeling of the 3β-HSD1 dimer identified a possible interaction between His156 on one subunit and Gln105 on the other. Kinetic analyses of the H156Y-1, Q105M-1 and Q105M-2 support subunit interactions that contribute to the higher affinity of 3β-HSD1 for the inhibitor, epostane, compared to 3β-HSD2. Article from the Special issue on Targeted Inhibitors.
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Selective inhibition of HSD3B1 slows down proliferation of a breast cancer cell line.
“Selective inhibition of HSD3B1 has been shown to slow down proliferation of breast cancer cell line and might just represent an interesting drug target simultaneously tackling androgen and oestrogen synthesis (Thomas et al., 2011).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Thomas et al., 2011
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- Authors
- Thomas, J. L., Bucholtz, K. M., & Kacsoh, B.
- Affiliations
- Mercer University (US)
- Corresponding author
- Thomas, James L.
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 125
- Issue
- 1-2
- Pages
- 57-65
- ISSN
- 0960-0760 (ISSN-L)
- PMC
- PMC2999670
- OpenAlex
- W1973859310
- Cited by
- 22
- References
- 42
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 3 · 2022: 1 · 2021: 1 · 2019: 1 · 2017: 5 · 2015: 1 · 2014: 3 · 2012: 2
- FWCI
- 0.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Queen Mary University of London
- National Institutes of Health
- National Cancer Institute (R01CA114717, CA114717)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- breast cancer, trilostane, epostane, competitive inhibition, subunit interactions, MCF-7 cells, postmenopausal women, enzyme structure modeling
- MeSH terms
- Breast Neoplasms, Cell Line, Female, Humans, Isoenzymes, Models, Molecular, Mutation, Protein Conformation, Steroids, 3-Hydroxysteroid Dehydrogenases, Molecular Structure
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