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T M Penning - One of the best experts on this subject based on the ideXlab platform.
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a 3 4 nitronaphthen 1 yl amino benzoate analog as a bifunctional AKR1C3 inhibitor and ar antagonist head to head comparison with other advanced AKR1C3 targeted therapeutics
The Journal of Steroid Biochemistry and Molecular Biology, 2019Co-Authors: Phumvadee Wangtrakuldee, Adegoke O Adeniji, Barry M Twenter, Jeffrey D Winkler, Tianzhu Zang, Ling Duan, Buddha B Khatri, Michelle A Estrada, Tyler F Higgins, T M PenningAbstract:Abstract Drugs used for the treatment of castration resistant prostate cancer (CRPC) include Abiraterone acetate (Zytiga®) and Enzalutamide (XTANDI®). However, these drugs provide clinical benefit in metastatic disease for only a brief period before drug resistance emerges. One mechanism of drug resistance involves the overexpression of type 5 17-β-hydroxysteroid dehydrogenase (aldo-keto reductase 1C3 or AKR1C3), a major enzyme responsible for the formation of intratumoral androgens that activate the androgen receptor (AR). 3-((4-Nitronaphthalen-1-yl)amino)benzoic acid 1 is a “first-in-class” AKR1C3 competitive inhibitor and AR antagonist. Compound 1 was compared in a battery of in vitro studies with structurally related N-naphthyl-aminobenzoates, and AKR1C3 targeted therapeutics e.g. GTx-560 and ASP9521, as well as with R-bicalutamide, enzalutamide and abiraterone acetate. Compound 1 was the only naphthyl derivative that was a selective AKR1C3 inhibitor and AR antagonist in direct competitive binding assays and in AR driven reporter gene assays. GTx-560 displayed weak activity as a direct AR antagonist but had high potency in the AR reporter gene assay consistent with its ability to inhibit the co-activator function of AKR1C3. By contrast ASP9521 did not act as either an AR antagonist or block AR reporter gene activity. Compound 1 was the only compound that showed comparable potency to inhibit AKR1C3 and act as a direct AR antagonist. Compound 1 blocked the formation of testosterone in LNCaP-AKR1C3 cells, and the expression of PSA driven by the AKR1C3 substrate (4-androstene-3,17-dione) and by an AR agonist, 5α-dihydrotestosterone consistent with its bifunctional role. Compound 1 blocked the nuclear translocation of the AR at similar concentrations to enzalutamide and caused disappearance of the AR from cell lysates. R-biaclutamide and enzalutamide inhibited AKR1C3 at concentrations 200x greater than compound 1, suggesting that its bifunctionality can be explained by a shared pharmacophore that can be optimized.
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AKR1C3 type 5 17β hydroxysteroid dehydrogenase prostaglandin f synthase roles in malignancy and endocrine disorders
Molecular and Cellular Endocrinology, 2019Co-Authors: T M PenningAbstract:Abstract Aldo-Keto-Reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase (HSD)/prostaglandin (PG) F2α synthase) is the only 17β-HSD that is not a short-chain dehydrogenase/reductase. By acting as a 17-ketosteroid reductase, AKR1C3 produces potent androgens in peripheral tissues which activate the androgen receptor (AR) or act as substrates for aromatase. AKR1C3 is implicated in the production of androgens in castration-resistant prostate cancer (CRPC) and polycystic ovarian syndrome; and is implicated in the production of aromatase substrates in breast cancer. By acting as an 11-ketoprostaglandin reductase, AKR1C3 generates 11β-PGF2α to activate the FP receptor and deprives peroxisome proliferator activator receptorγ of its putative PGJ2 ligands. These growth stimulatory signals implicate AKR1C3 in non-hormonal dependent malignancies e.g. acute myeloid leukemia (AML). AKR1C3 moonlights by acting as a co-activator of the AR and stabilizes ubiquitin ligases. AKR1C3 inhibitors have been used clinically for CRPC and AML and can be used to probe its pluripotency.
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potent and highly selective aldo keto reductase 1c3 AKR1C3 inhibitors act as chemotherapeutic potentiators in acute myeloid leukemia and t cell acute lymphoblastic leukemia
Journal of Medicinal Chemistry, 2019Co-Authors: Kshitij Verma, T M Penning, Tianzhu Zang, Paul C TrippierAbstract:Aldo–keto reductase 1C3 (AKR1C3) catalyzes the synthesis of 9α,11β-prostaglandin (PG) F2α and PGF2α prostanoids that sustain the growth of myeloid precursors in the bone marrow. The enzyme is overexpressed in acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). Moreover, AKR1C3 confers chemotherapeutic resistance to the anthracyclines: first-line agents for the treatment of leukemias. The highly homologous isoforms AKR1C1 and AKR1C2 inactivate 5α-dihydrotestosterone, and their inhibition would be undesirable. We report herein the identification of AKR1C3 inhibitors that demonstrate exquisite isoform selectivity for AKR1C3 over the other closely related isoforms to the order of >2800-fold. Biological evaluation of our isoform-selective inhibitors revealed a high degree of synergistic drug action in combination with the clinical leukemia therapeutics daunorubicin and cytarabine in in vitro cellular models of AML and primary patient-derived T-ALL cells. Our developed compounds exhibi...
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screening baccharin analogs as selective inhibitors against type 5 17β hydroxysteroid dehydrogenase AKR1C3
Chemico-Biological Interactions, 2015Co-Authors: Tianzhu Zang, Mo Chen, Kshitij Verma, Paul C Trippier, T M PenningAbstract:Abstract Aldo–keto reductase 1C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase, is a downstream steroidogenic enzyme and converts androgen precursors to the potent androgen receptor ligands: testosterone and 5α-dihydrotestosterone. Studies have shown that AKR1C3 is involved in the development of castration resistant prostate cancer (CRPC) and that it is a rational drug target for the treatment of CRPC. Baccharin, a component of Brazilian propolis, has been observed to exhibit a high inhibitory potency and selectivity for AKR1C3 over other AKR1C isoforms and is a promising lead compound for developing more potent and selective inhibitors. Here, we report the screening of fifteen baccharin analogs as selective inhibitors against AKR1C3 versus AKR1C2 (type 3 3α-hydroxysteroid dehydrogenase). Among these analogs, the inhibitory activity and selectivity of thirteen compounds were evaluated for the first time. The substitution of the 4-dihydrocinnamoyloxy group of baccharin by an acetate group displayed nanomolar inhibitory potency (IC50: 440 nM) and a 102-fold selectivity over AKR1C2. By contrast, when the cinnamic acid group of baccharin was esterified, there was a dramatic decrease in potency and selectivity for AKR1C3 in comparison to baccharin. Low or sub-micromolar inhibition was observed when the 3-prenyl group of baccharin was removed, and the selectivity over AKR1C2 was low. Although unsubstituted baccharin was still the most potent (IC50: 100 nM) and selective inhibitor for AKR1C3, these data provide structure–activity relationships required for the optimization of new baccharin analogs. They suggest that the carboxylate group on cinnamic acid, the prenyl group, and either retention of 4-dihydrocinnamoyloxy group or acetate substituent on cinnamic acid are important to maintain the high potency and selectivity for AKR1C3.
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AKR1C3 as a target in castrate resistant prostate cancer
The Journal of Steroid Biochemistry and Molecular Biology, 2013Co-Authors: Adegoke O Adeniji, Mo Chen, T M PenningAbstract:Abstract Aberrant androgen receptor (AR) activation is the major driver of castrate resistant prostate cancer (CRPC). CRPC is ultimately fatal and more therapeutic agents are needed to treat this disease. Compounds that target the androgen axis by inhibiting androgen biosynthesis and or AR signaling are potential candidates for use in CRPC treatment and are currently being pursued aggressively. Aldo-keto reductase 1C3 (AKR1C3) plays a pivotal role in androgen biosynthesis within the prostate. It catalyzes the 17-ketoreduction of weak androgen precursors to give testosterone and 5α-dihydrotestosterone. AKR1C3 expression and activity has been implicated in the development of CRPC, making it a rational target. Selective inhibition of AKR1C3 will be important, however, due to the presence of closely related isoforms, AKR1C1 and AKR1C2 that are also involved in androgen inactivation. We examine the evidence that supports the vital role of AKR1C3 in CRPC and recent developments in the discovery of potent and selective AKR1C3 inhibitors. This article is part of a Special Issue entitled ‘CSR 2013’.
Kar Ming Fung - One of the best experts on this subject based on the ideXlab platform.
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Original Article Expression of aldo-keto reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung
2020Co-Authors: Theodore S Chang, Lacy S Brame, Qing Yang, Kyle A Rogers, Kar Ming FungAbstract:Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reduc - ing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and ad- enocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tis- sue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3's role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.
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expression of aldo keto reductase family 1 member c3 AKR1C3 in neuroendocrine tumors adenocarcinomas of pancreas gastrointestinal tract and lung
International Journal of Clinical and Experimental Pathology, 2013Co-Authors: Theodore S Chang, Lacy S Brame, Qing Yang, Kyle A Rogers, Kar Ming FungAbstract:Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and adenocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tissue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3’s role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.
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Expression of aldo-keto reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung.
International Journal of Clinical and Experimental Pathology, 2013Co-Authors: Theodore S Chang, Lacy S Brame, Qing Yang, Kyle A Rogers, Kar Ming FungAbstract:Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and adenocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tissue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3’s role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.
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aldo keto reductase family 1 member c3 AKR1C3 is expressed in adenocarcinoma and squamous cell carcinoma but not small cell carcinoma
International Journal of Clinical and Experimental Pathology, 2012Co-Authors: Valerie L Miller, T M Penning, Qing Yang, Paari Murugan, Lacy S Brame, Kar Ming FungAbstract:Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17β-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids including estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin reductase activity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endometrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demonstrated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junction. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunoreactivity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma pathogenesis require further studies.
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original article aldo keto reductase family 1 member c3 AKR1C3 is expressed in adenocarcinoma and squamous cell car cinoma but not small cell carcinoma
2012Co-Authors: Valerie L Miller, T M Penning, Qing Yang, Paari Murugan, Lacy S Brame, Kar Ming FungAbstract:Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17β-diol (3α-diol) and oxidizing 3α-diol to androster- one. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17β-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids includ- ing estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin reductase activ- ity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endo- metrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demon- strated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junc- tion. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunore- activity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma patho- genesis require further studies.
Joseph Azzarello - One of the best experts on this subject based on the ideXlab platform.
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elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell mediated endothelial cell tube formation implications for prostate cancer progressioan
BMC Cancer, 2010Co-Authors: Mikhail G Dozmorov, Kar Ming Fung, Joseph Azzarello, Qing Yang, Jonathan D Wren, Jeffrey S Davis, Robert E Hurst, Daniel J Culkin, T M PenningAbstract:Background Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR1C enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we propose a novel pathological function of AKR1C3 in tumor angiogenesis and its potential role in promoting PCa progression.
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expression of AKR1C3 in renal cell carcinoma papillary urothelial carcinoma and wilms tumor
International Journal of Clinical and Experimental Pathology, 2010Co-Authors: Joseph Azzarello, T M Penning, Daniel J Culkin, Bradley P Kropp, Awet Gherezghiher, Vladislav Zakharov, Zhongxin Yu, Kar Ming FungAbstract:Human aldo-keto reductase (AKR) 1C3 is a monomeric cytoplasmic multifunctional enzyme that reduces ketosteroids, ketoprostaglandins, and lipid aldehydes. AKR1C3 was initially identified as an enzyme involved in steroid metabolism. However, immunohistochemistry has demonstrated AKR1C3 in normal adult kidneys with expression in Bowman' capsule, the mesangial cells, proximal and distal tubules, as well as mature urothelial epithelium. The significance of its spatial distribution and metabolic activities in the kidney remains undefined. In addition to its ability to catalyze steroid hormones (including androgen, desoxycorticosterone, and progesterone) and involvement in prostaglandins metabolism, we suspect that AKR1C3 may function as a chemical barrier in the renal tubules for normal function in mature kidneys. Moreover, AKR1C3 may represent a developmental marker for some urological epithelial tissues. In this study, we demonstrate widespread expression of AKR1C3 in renal neoplasms with a phenotype recapitulating mature kidney (i.e., renal cell carcinoma) and urothelium also known as transitional epithelium (i.e., papillary urothelial carcinoma), but noted limited AKR1C3 expression in renal neoplasms with a phenotype recapitulating embryonic kidneys (i.e., Wilms' tumor). Our results suggest that AKR1C3 may represent a developmental marker that is related to renal epithelium maturity.
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suppressed expression of type 2 3α type 5 17β hydroxysteroid dehydrogenase AKR1C3 in endometrial hyperplasia and carcinoma
International Journal of Clinical and Experimental Pathology, 2010Co-Authors: Vladislav Zakharov, T M Penning, Joseph Azzarello, Scott Mcmeekin, Kathleen N Moore, Kar Ming FungAbstract:The diagnosis of endometrial hyperplasia and endometrial type adenocarcinoma arising within the uterine cavity has long been rested on morphologic criteria. Although distinction between normal endometrial epithelium from adenocarcinoma is usually straightforward, the separation between normal and hyperplastic endometrium, particularly those cases without atypia, can be a diagnostic challenge. The same is true in separation of hyperplastic endometrium with atypia from endometrial-type endometrial adenocarcinoma. Type 2 3α-/type 5 17β-hydroxysteroid dehydrogenase (HSD) (AKR1C3) is a multifunctional enzyme involved in androgen, estrogen, progesterone, and pros-taglandin metabolism. Its expression has been shown in the epithelium of the renal tubules, urothelial epithelium, and endothelial cells in normal tissues as well as in prostatic adenocarcinoma. The proliferation and maintenance of endometrial epithelium is dependent on both estrogen and progesterone; and AKR1C3-mediated steroid metabolism may play a critical role in the maintenance of viable normal and abnormal endometrial epithelium. We studied the expression of AKR1C3 in 33 endometrial biopsy specimens including 13 cases of normal proliferative endometrium, 8 cases of hyperplastic endometrium with and without atypia, and 12 cases of primary endometrial adenocarcinoma of endometrial type. We demonstrated a uniform, diffuse, and strong expression of AKR1C3 in normal endometrial epithelium but not in endometrial stromal cells. In contrast, the expression of AKR1C3 is reduced in both hyperplastic and carcinomatous endometrial epithelium. These findings suggest that AKR1C3 may play important roles in the physiology of endometrial cells and that suppressed AKR1C3 expression may represent a feature that allows differentiation of hyperplastic and neoplastic endometrial epithelium from normal endometrial epithelium. However, reduced AKR1C3 expression cannot distinguish hyperplastic endometrium from endometrial adenocarcinoma of endometrial type. The biologic and pathological roles of AKR1C3 in endometrial epithelium require further investigation.
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Suppressed expression of type 2 3α/type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) in endometrial hyperplasia and carcinoma
International Journal of Clinical and Experimental Pathology, 2010Co-Authors: Vladislav Zakharov, Trevor M. Penning, Joseph Azzarello, Scott Mcmeekin, Kathleen N Moore, Kar Ming FungAbstract:The diagnosis of endometrial hyperplasia and endometrial type adenocarcinoma arising within the uterine cavity has long been rested on morphologic criteria. Although distinction between normal endometrial epithelium from adenocarcinoma is usually straightforward, the separation between normal and hyperplastic endometrium, particularly those cases without atypia, can be a diagnostic challenge. The same is true in separation of hyperplastic endometrium with atypia from endometrial-type endometrial adenocarcinoma. Type 2 3α-/type 5 17β-hydroxysteroid dehydrogenase (HSD) (AKR1C3) is a multifunctional enzyme involved in androgen, estrogen, progesterone, and pros-taglandin metabolism. Its expression has been shown in the epithelium of the renal tubules, urothelial epithelium, and endothelial cells in normal tissues as well as in prostatic adenocarcinoma. The proliferation and maintenance of endometrial epithelium is dependent on both estrogen and progesterone; and AKR1C3-mediated steroid metabolism may play a critical role in the maintenance of viable normal and abnormal endometrial epithelium. We studied the expression of AKR1C3 in 33 endometrial biopsy specimens including 13 cases of normal proliferative endometrium, 8 cases of hyperplastic endometrium with and without atypia, and 12 cases of primary endometrial adenocarcinoma of endometrial type. We demonstrated a uniform, diffuse, and strong expression of AKR1C3 in normal endometrial epithelium but not in endometrial stromal cells. In contrast, the expression of AKR1C3 is reduced in both hyperplastic and carcinomatous endometrial epithelium. These findings suggest that AKR1C3 may play important roles in the physiology of endometrial cells and that suppressed AKR1C3 expression may represent a feature that allows differentiation of hyperplastic and neoplastic endometrial epithelium from normal endometrial epithelium. However, reduced AKR1C3 expression cannot distinguish hyperplastic endometrium from endometrial adenocarcinoma of endometrial type. The biologic and pathological roles of AKR1C3 in endometrial epithelium require further investigation.
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tissue distribution of human AKR1C3 and rat homolog in the adult genitourinary system
Journal of Histochemistry and Cytochemistry, 2008Co-Authors: Joseph Azzarello, Kar Ming FungAbstract:Human aldo-keto reductase (AKR) 1C3 (type 2 3α-hydroxysteroid dehydrogenase/type 5 17β-hydroxysteroid dehydrogenase) catalyzes androgen, estrogen, and prostaglandin metabolism. AKR1C3 is therefore implicated in regulating ligand access to the androgen receptor, estrogen receptor, and peroxisome proliferator activating receptor γ in hormone target tissues. Recent reports on close relationships between ARK1C3 and various cancers including breast and prostate cancers implicate the involvement of AKR1C3 in cancer development or progression. We previously described the characterization of an isoform-specific monoclonal antibody against AKR1C3 that does not cross-react with related, >86% sequence identity, human AKR1C1, AKR1C2, or AKR1C4, human aldehyde reductase AKR1A1, or rat 3α-hydroxysteroid dehydrogenase (AKR1C9). In this study, a clone of murine monoclonal antibody raised against AKR1C3 was identified and characterized for its recognition of rat homolog. Tissue distribution of human AKR1C3 and its rat homolog in adult genitourinary systems including kidney, bladder, prostate, and testis was studied by IHC. A strong immunoreactivity was detected not only in classically hormone-associated tissues such as prostate and testis but also in non–hormone-associated tissues such as kidney and bladder in humans and rats. The distribution of these two enzymes was comparable but not identical between the two species. These features warrant future studies of AKR1C3 in both hormone- and non–hormone-associated tissues and identification of the rodent homolog for establishing animal models. (J Histochem Cytochem 56:853–861, 2008)
Qing Yang - One of the best experts on this subject based on the ideXlab platform.
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Original Article Expression of aldo-keto reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung
2020Co-Authors: Theodore S Chang, Lacy S Brame, Qing Yang, Kyle A Rogers, Kar Ming FungAbstract:Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reduc - ing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and ad- enocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tis- sue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3's role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.
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expression of aldo keto reductase family 1 member c3 AKR1C3 in neuroendocrine tumors adenocarcinomas of pancreas gastrointestinal tract and lung
International Journal of Clinical and Experimental Pathology, 2013Co-Authors: Theodore S Chang, Lacy S Brame, Qing Yang, Kyle A Rogers, Kar Ming FungAbstract:Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and adenocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tissue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3’s role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.
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Expression of aldo-keto reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung.
International Journal of Clinical and Experimental Pathology, 2013Co-Authors: Theodore S Chang, Lacy S Brame, Qing Yang, Kyle A Rogers, Kar Ming FungAbstract:Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and adenocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tissue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3’s role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.
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aldo keto reductase family 1 member c3 AKR1C3 is expressed in adenocarcinoma and squamous cell carcinoma but not small cell carcinoma
International Journal of Clinical and Experimental Pathology, 2012Co-Authors: Valerie L Miller, T M Penning, Qing Yang, Paari Murugan, Lacy S Brame, Kar Ming FungAbstract:Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17β-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids including estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin reductase activity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endometrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demonstrated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junction. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunoreactivity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma pathogenesis require further studies.
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original article aldo keto reductase family 1 member c3 AKR1C3 is expressed in adenocarcinoma and squamous cell car cinoma but not small cell carcinoma
2012Co-Authors: Valerie L Miller, T M Penning, Qing Yang, Paari Murugan, Lacy S Brame, Kar Ming FungAbstract:Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17β-diol (3α-diol) and oxidizing 3α-diol to androster- one. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17β-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids includ- ing estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin reductase activ- ity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endo- metrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demon- strated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junc- tion. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunore- activity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma patho- genesis require further studies.
Trevor M. Penning - One of the best experts on this subject based on the ideXlab platform.
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AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase): Roles in malignancy and endocrine disorders
Molecular and Cellular Endocrinology, 2018Co-Authors: Trevor M. PenningAbstract:Abstract Aldo-Keto-Reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase (HSD)/prostaglandin (PG) F2α synthase) is the only 17β-HSD that is not a short-chain dehydrogenase/reductase. By acting as a 17-ketosteroid reductase, AKR1C3 produces potent androgens in peripheral tissues which activate the androgen receptor (AR) or act as substrates for aromatase. AKR1C3 is implicated in the production of androgens in castration-resistant prostate cancer (CRPC) and polycystic ovarian syndrome; and is implicated in the production of aromatase substrates in breast cancer. By acting as an 11-ketoprostaglandin reductase, AKR1C3 generates 11β-PGF2α to activate the FP receptor and deprives peroxisome proliferator activator receptorγ of its putative PGJ2 ligands. These growth stimulatory signals implicate AKR1C3 in non-hormonal dependent malignancies e.g. acute myeloid leukemia (AML). AKR1C3 moonlights by acting as a co-activator of the AR and stabilizes ubiquitin ligases. AKR1C3 inhibitors have been used clinically for CRPC and AML and can be used to probe its pluripotency.
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Development of Potent and Selective Indomethacin Analogues for the Inhibition of AKR1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase/Prostaglandin F Synthase) in Castrate-Resistant Prostate Cancer
Journal of Medicinal Chemistry, 2013Co-Authors: Andy J Liedtke, Adegoke O Adeniji, Mo Chen, Michael C Byrns, David W Christianson, Lawrence J Marnett, Trevor M. PenningAbstract:Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5α-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3·NADP+·2′-des-methyl-indomethacin crystal structur...
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N-Benzoyl anthranilic acid derivatives as selective inhibitors of aldo–keto reductase AKR1C3
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Masa Sinreih, Trevor M. Penning, Samo Turk, Adegoke O Adeniji, Tea Lanisnik Rižner, Izidor Sosic, Natasa Beranic, Stanislav GobecAbstract:Abstract Human aldo–keto reductases AKR1C1–AKR1C3 are involved in the biosynthesis and inactivation of steroid hormones and prostaglandins and thus represent attractive targets for the development of new drugs. We synthesized a series of N -benzoyl anthranilic acid derivatives and tested their inhibitory activity on AKR1C enzymes. Our data show that these derivatives inhibit AKR1C1–AKR1C3 isoforms with low micromolar potency. In addition, five selective inhibitors of AKR1C3 were identified. The most promising inhibitors were compounds 10 and 13 , with IC 50 values of 0.31 μM and 0.35 μM for AKR1C3, respectively.
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abstract b16 development of potent and selective indomethacin analogs for the inhibition of AKR1C3 type 5 17β hydroxysteroid dehydrogenase in crpc
Cancer Research, 2012Co-Authors: Adegoke O Adeniji, Mo Chen, Michael C Byrns, David W Christianson, Lawrence J Marnett, Andrew Liedkte, Trevor M. PenningAbstract:Abstract Castrate-resistant prostate cancer (CRPC) is a fatal metastatic form of prostate cancer that accounts for 30,000 deaths in the U.S. annually. Patients with advanced prostate cancer that initially respond to hormonal ablative therapy (orchiectomy or chemical castration) invariably develop CRPC. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor (AR) signaling and/or adaptive intratumoral androgen biosynthesis. The latter is targeted with the new agent abiraterone acetate (a P450 17α-hydroxylase/17,20-lyase inhibitor) which prevents the production of the adrenal androgen precursor, dehydroepiandrosterone but has the unintended consequence of building up the potent mineralocortcoid, desoxycorticosterone. To circumvent this side effect, abiraterone acetate is co-administered with prednisone. AKR1C3 is among the most upregulated genes in CRPC and in soft tissue metastasis where its 17β-hydroxysteroid dehydrogenase activity converts the weak androgens, 4-androstene-3,17-dione and 5α-androstane-3,17-dione to the potent androgens, testosterone and 5α-dihydrotestosterone, respectively. The role of AKR1C3 in the pre-receptor regulation of ligands for the AR makes it a more selective target than abiraterone for the treatment of CRPC. Inhibitors of AKR1C3 should not inhibit the related isoforms, AKR1C1 and AKR1C2 since these enzymes inactivate 5α-dihydrotestosterone. Indomethacin, a therapeutic agent used to inhibit cyclooxygenase (COX) also inhibits AKR1C3 potently and displays selectivity over AKR1C1 and AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogs which based on known structure-activity relationships should no longer inhibit COX enzymes but may retain AKR1C3 inhibitory potency and selectivity. Three classes of AKR1C3 inhibitors were discovered, that had the desired properties: indomethacin analogs (in which the 3′-side chain was modified), 2′-desmethyl-indomethacin analogs (which had either an acid or trifluoromethylsulfonamide substituent at the 3′-position), and 3′-alkyl-indomethacin analogs (which had either an acid or trifluoromethylsulfonamide substituent at the 2′-position). The lead compounds inhibited AKR1C3 with nanomolar potency, displayed over 100-fold selectivity for AKR1C3 over AKR1C1/AKR1C2 and produced robust inhibition of testosterone formation in an LNCaP-AKR1C3 prostate cancer cell line. Several had minimal inhibitory affects on COX-1 and COX-2. In a separate study, indomethacin blocked PSA and ERG expression, and cell proliferation in a VCaP xenograft model of CRPC providing in vivo efficacy data (Cai at al., Cancer Res. 71: 6503, 2011). 2′-Desmethyl-indomethacin 1 was crystallized in complex with AKR1C3 and NADP+, and diffraction data were obtained at 1.8 A resolution. The structure showed that in the absence of the 2′-methyl group the compound assumes a different binding mode to indomethacin. Compound 1 binds perpendicular to indomethacin such that the carboxylic acid on its indole ring is tethered to the oxyanion site and protrudes into a SP1 pocket as seen with the other NSAIDs like flufenamic acid. This model provides a binding pose for the 2′-desmethyl indomethacin analogs and also predicts a possible binding pose for the 3′-alkyl indomethacin series. The compounds reported are promising agents for the preclinical development of therapeutics for CRPC, which by targeting AKR1C3 will be more selective than P450 17α-hydroxylase/17,20-lyase inhibitors, and will not have to be co-administered with prednisone. The agents disclosed in this abstract are protected by US Provisional Patent Application No. 61/548,004. [Supported by R01-CA90744 and a Prostate Cancer Foundation Challenge Award to TMP and R01-CA889450 to LJM] Citation Format: Adegoke Adeniji, Andrew Liedkte, Michael C. Byrns, M Chen, Yi Jin, David Christianson, Lawrence J. Marnett, Trevor M. Penning. Development of potent and selective indomethacin analogs for the inhibition of AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase) in CRPC [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B16.
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Suppressed expression of type 2 3α/type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) in endometrial hyperplasia and carcinoma
International Journal of Clinical and Experimental Pathology, 2010Co-Authors: Vladislav Zakharov, Trevor M. Penning, Joseph Azzarello, Scott Mcmeekin, Kathleen N Moore, Kar Ming FungAbstract:The diagnosis of endometrial hyperplasia and endometrial type adenocarcinoma arising within the uterine cavity has long been rested on morphologic criteria. Although distinction between normal endometrial epithelium from adenocarcinoma is usually straightforward, the separation between normal and hyperplastic endometrium, particularly those cases without atypia, can be a diagnostic challenge. The same is true in separation of hyperplastic endometrium with atypia from endometrial-type endometrial adenocarcinoma. Type 2 3α-/type 5 17β-hydroxysteroid dehydrogenase (HSD) (AKR1C3) is a multifunctional enzyme involved in androgen, estrogen, progesterone, and pros-taglandin metabolism. Its expression has been shown in the epithelium of the renal tubules, urothelial epithelium, and endothelial cells in normal tissues as well as in prostatic adenocarcinoma. The proliferation and maintenance of endometrial epithelium is dependent on both estrogen and progesterone; and AKR1C3-mediated steroid metabolism may play a critical role in the maintenance of viable normal and abnormal endometrial epithelium. We studied the expression of AKR1C3 in 33 endometrial biopsy specimens including 13 cases of normal proliferative endometrium, 8 cases of hyperplastic endometrium with and without atypia, and 12 cases of primary endometrial adenocarcinoma of endometrial type. We demonstrated a uniform, diffuse, and strong expression of AKR1C3 in normal endometrial epithelium but not in endometrial stromal cells. In contrast, the expression of AKR1C3 is reduced in both hyperplastic and carcinomatous endometrial epithelium. These findings suggest that AKR1C3 may play important roles in the physiology of endometrial cells and that suppressed AKR1C3 expression may represent a feature that allows differentiation of hyperplastic and neoplastic endometrial epithelium from normal endometrial epithelium. However, reduced AKR1C3 expression cannot distinguish hyperplastic endometrium from endometrial adenocarcinoma of endometrial type. The biologic and pathological roles of AKR1C3 in endometrial epithelium require further investigation.
