AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer
Abstract
Endometrial cancer is the most common malignancy of the female genital tract. Its incidence correlates with prolonged estrogen stimulation unopposed by progesterone or synthetic progestins. Estrogen and progestin action is regulated at the pre-receptor level, by interconversion of active hormones (estradiol (E2), progesterone (P)) with their inactive counterparts (estrone (E1), 20alpha-hydroxyprogesterone (20alpha-OHP)) in target tissues. Expression of enzymes that control the ratio of E2 and P may thus play role in the disease process. We first confirmed that AKR1C1 (human 20alpha-hydroxysteroid dehydrogenase) in a cellular context inactivates P by forming 20alpha-OHP but does not catalyze the reverse reaction. We next examined the expression of AKR1C1 and AKR1C3 (type 5 17beta-hydroxysteroid dehydrogenase) in 16 paired specimens of endometrial cancer and adjacent normal endometrium. Quantification by isoform specific real-time PCR revealed higher expression of AKR1C1 in nine specimens and higher expression of AKR1C3 in four specimens of endometrial cancer. Importantly, upregulation of both enzymes in the same specimen was observed. Since AKR1C1 inactivates P its elevated expression in diseased endometrium may contribute to diminished protection by P, while elevated expression of AKR1C3 which forms E2 in vivo, may contribute to the enhanced estrogen action. It is suggested that the expression of AKR1C1 and AKR1C3 in endometrial cancer will govern the ratio of P:E2.
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Direct 20α-reduction of progesterone terminates its progestogenic activity.
“the direct 20α-reduction of progesterone terminates its progestogenic activity”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [115]
Direct 20α-reduction of progesterone is predominantly catalyzed by AKR1C1.
“is predominantly catalyzed by AKR1C1 [104,115].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [115]
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Self-citation
- Authors
- Rižner, T. L., Šmuc, T., Rupreht, R., Šinkovec, J., & Penning, T. M.
- Affiliations
- University of Ljubljana (SI)
- Blood Transfusion Centre of Slovenia (SI)
- Ljubljana University Medical Centre (SI)
- University of Pennsylvania (US)
- Corresponding author
- Rižner, Tea Lanišnik
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2006-03
- Volume
- 248
- Issue
- 1-2
- Pages
- 126-135
- ISSN
- 0303-7207 (ISSN-L)
- OpenAlex
- W2032301907
- Cited by
- 159
- References
- 33
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 7 · 2023: 4 · 2022: 6 · 2021: 13 · 2020: 6 · 2019: 11 · 2018: 5 · 2017: 8 · 2016: 6 · 2015: 5 · 2014: 14 · 2013: 8 · 2012: 12
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA090744)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- endometrial cancer, AKR1C1, AKR1C3, 20α-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, progesterone, estradiol, estrogen-progesterone ratio, 20alpha-dihydroprogesterone, steroid hormone metabolism, gene expression
- MeSH terms
- Aldo-Keto Reductase Family 1 Member C3, Animals, Endometrium, Estradiol, Estradiol Dehydrogenases, Estrogens, Female, Humans, Hydroxyprostaglandin Dehydrogenases, Isoenzymes, Oxidoreductases, Progesterone, Tumor Cells, Cultured, 17-Hydroxysteroid Dehydrogenases, 20-Hydroxysteroid Dehydrogenases, 3-Hydroxysteroid Dehydrogenases, Endometrial Neoplasms
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