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Nima Sharifi - One of the best experts on this subject based on the ideXlab platform.
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SAT-734 HSD3B1 Expression in the Human Immune System
Journal of the Endocrine Society, 2020Co-Authors: Jeffrey M Mcmanus, Thi Hong Nga Le, Kewal Asosingh, Joe Zein, Serpil Erzurum, Nima SharifiAbstract:Abstract 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), catalyzing conversion of dehydroepiandrosterone (DHEA) to Δ 4-androstenedione, is an essential enzyme in the pathway toward production of biologically active androgens such as dihydrotestosterone from the adrenally produced precursor DHEA sulfate, the most predominant steroid hormone in circulation. We previously identified, in the gene (HSD3B1) that encodes 3βHSD1, a germline gain-of-function missense-encoding variant that has now been validated in several studies as predicting more rapid progression in prostate cancer patients treated with gonadal testosterone deprivation. Production of androgens from adrenal precursors is important not just in the context of prostate cancer but in other physiologic and pathophysiologic processes, which could include asthma. Androgens are associated with better lung function in both asthma and healthy cohorts, and increasing circulating androgen levels in males help explain the switchover in asthma being more common in boys than girls but then more common in women than men. A main treatment for asthma, as well as other inflammatory processes, is administration of glucocorticoids, yet unresponsiveness to glucocorticoids in a subset of patients remains a major problem. Systemic glucocorticoid administration suppresses adrenally produced DHEA and DHEA-S, suggesting a depleted pool for biologically active androgen production as a mechanism for glucocorticoid resistance. Our surprising preliminary data support a link between glucocorticoid responsiveness and the more active HSD3B1 allele: patients homozygous for the adrenal-permissive HSD3B1(1245C) allele exhibit better response to oral glucocorticoids than those homozygous for the adrenal-restrictive HSD3B1(1245A), with heterozygous patients falling in the middle. This suggests a model in which patients with the more active (adrenal-permissive) form of 3βHSD1 produce sufficient androgens despite the depleted pool of precursor hormones whereas patients with the less active (adrenal-restrictive) form cannot. To further elucidate the link between 3βHSD1 activity and immune response, we assayed HSD3B1 expression in different types of white blood cells. Leukocyte subsets from asthma patients and healthy controls were purified using fluorescence-activated cell sorting, and HSD3B1 expression was analyzed using qPCR. White blood cells of several types expressed HSD3B1 at levels comparable to or greater than both prostate cancer and placental choriocarcinoma cell lines with very robust 3βHSD1 activity. Further determining the cell type specific expression and activity of this key enzyme is an important step in unraveling the link between the HSD3B1 polymorphism and asthma along with potentially many other immune processes.
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HSD3B1 genotypes conferring adrenal restrictive and adrenal permissive phenotypes in prostate cancer and beyond
Endocrinology, 2019Co-Authors: Navin C Sabharwal, Nima SharifiAbstract:: Castration-resistant prostate cancer (PCa) almost invariably occurs after androgen deprivation therapy for metastatic disease and is driven in part by androgen synthesis within the tumor. 3β-hydroxysteroid dehydrogenase isoenzyme-1 catalyzes the conversion of adrenal precursor steroids into potent androgens essential for PCa progression. A common 1245 A→C missense-encoding single nucleotide polymorphism in HSD3B1 (rs1047303), the gene that encodes this enzyme, leads to a more stable protein that is resistant to degradation and thus increased production of potent androgens from adrenal precursors, facilitating castration-resistant PCa development. Consistent with this mechanism, this adrenal-permissive HSD3B1(1245C) genotype is associated with inferior outcomes after androgen deprivation therapy for advanced PCa, and increased sensitivity to pharmacologic blockade of adrenal precursors in metastatic disease. Herein, we review current knowledge of the mechanisms conferred by HSD3B1 genotype to alter androgen physiology and accelerate development of castration-resistant disease and its associations with clinical PCa outcomes. In light of its effect on steroid physiology, we also discuss its potential associations with non-PCa phenotypes.
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3βhsd1 immunohistochemistry and HSD3B1 genotype in prostate cancer
Journal of Clinical Oncology, 2019Co-Authors: J Haijing J Zhang, Daniel Hettel, Marlo Nicolas, Aimalie Hardaway, Kelsey Bohn, Eric A Klein, Nima SharifiAbstract:277Background: 3β-hydroxysteroid dehydrogenase (3βHSD1), encoded by HSD3B1, catalyzes intratumoral androgen synthesis from adrenal precursors. The HSD3B1(1245A>C) germline variant encodes a more stable enzyme that promotes increased DHT synthesis and more rapid clinical progression in men treated with androgen deprivation therapy (ADT). 3βHSD1 localization and expression in prostate tissue has not been rigorously characterized. We hypothesized that HSD3B1 homozygous variant genotype is associated with elevated 3βHSD1 immunoreactivity compared with wild-type (WT) genotype. Methods: In a pilot study, HSD3B1 genotypes were obtained from prostatectomy tissues of 30 patients with prostate cancer (10 WT, 10 heterozygous, and 10 homozygous variant). Following prostatectomy, tumor tissue with adjacent benign prostate was formalin-fixed and paraffin-embedded. Immunostaining for 3βHSD1 using a validated mouse monoclonal antibody was performed. Human placenta was used as a positive control. Immunostaining patterns a...
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ar signaling in prostate cancer regulates a feed forward mechanism of androgen synthesis by way of HSD3B1 upregulation
Endocrinology, 2018Co-Authors: Daniel Hettel, Ao Zhang, Mohammad Alyamani, Michael Berk, Nima SharifiAbstract:: 3βHSD1 enzymatic activity is essential for synthesis of potent androgens from adrenal precursor steroids in prostate cancer. A germline variant in HSD3B1, the gene that encodes 3βHSD1, encodes for a stable enzyme, regulates adrenal androgen dependence, and is a predictive biomarker of poor clinical outcomes after gonadal testosterone deprivation therapy. However, little is known about HSD3B1 transcriptional regulation. Generally, it is thought that intratumoral androgen synthesis is upregulated after gonadal testosterone deprivation, enabling development of castration-resistant prostate cancer. Given its critical role in extragonadal androgen synthesis, we sought to directly interrogate the transcriptional regulation of HSD3B1 in multiple metastatic prostate cancer cell models. Surprisingly, we found that VCaP, CWR22Rv1, LNCaP, and LAPC4 models demonstrate induction of HSD3B1 upon androgen stimulation for approximately 72 hours, followed by attenuation around 120 hours. 3βHSD1 protein levels mirrored transcriptional changes in models harboring variant (LNCaP) and wild-type (LAPC4) HSD3B1, and in these models androgen induction of HSD3B1 is abrogated via enzalutamide treatment. Androgen treatment increased flux from [3H]-dehydroepiandrosterone to androstenedione and other downstream metabolites. HSD3B1 expression was reduced 72 hours after castration in the VCaP xenograft mouse model, suggesting androgen receptor (AR) regulation of HSD3B1 also occurs in vivo. Overall, these data suggest that HSD3B1 is unexpectedly positively regulated by androgens and ARs. These data may have implications for the development of treatment strategies tailored to HSD3B1 genotype status.
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HSD3B1 status as a biomarker of androgen deprivation resistance and implications for prostate cancer
Nature Reviews Urology, 2018Co-Authors: Daniel Hettel, Nima SharifiAbstract:Hettel and Sharifi discuss how germline HSD3B1 1245A>C variant status influences outcomes of men with prostate cancer receiving androgen deprivation therapy, indicating its utility as a predictive biomarker. Metabolic effects of variant HSD3B1 status highlight a potential requirement to modify current treatment frameworks.
Yungming Jeng - One of the best experts on this subject based on the ideXlab platform.
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HSD3B1 is a specific trophoblast associated marker not expressed in a wide spectrum of tumors
International Journal of Gynecological Cancer, 2013Co-Authors: Yuhyu Chou, Yungming JengAbstract:Objective Hydroxyl-δ-5-steroid dehydrogenase (HSD3B1) is an enzyme that catalyzes the oxidative conversion of δ-5-3 β-hydroxyl steroids to the δ-4-3-keto configuration and is involved in steroid hormone synthesis. It has been shown to be expressed in normal trophoblastic tissue and benign and neoplastic trophoblastic lesions. HSD3B1 has not been detected in a large number of lung, breast, and uterine carcinomas; however, its expression has not been studied in a wide variety of other nontrophoblastic neoplasms. To test if HSD3B1 is highly specific for normal trophoblasts and trophoblast-associated lesions, we examined the expression of HSD3B1 in a wide spectrum of tumors. Methods Tissue microarrays containing 473 carcinomas from the lung, breast, ovary, uterus, liver, pancreas, stomach, and colon; 32 ovarian granulose cell tumors; and 12 adrenocortical adenomas were studied by immunohistochemistry using a commercially available monoclonal antibody, HSD3B1. One tissue microarray containing normal tissues was also included. Positive staining of intermediate trophoblasts and syncytiotrophoblasts in normal placental tissue served as a positive control. Results Normal tissues and tumors from the various sites were all negative for HSD3B1 except for 2 adrenocortical adenomas with weak focal immunoreactivity. Conclusions Our study further confirmed that HSD3B1 is a highly specific trophoblast-associated marker that can be used in the distinction of trophoblastic tumorlike lesions and tumors from nontrophoblastic lesions and tumors.
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HSD3B1 as a novel trophoblast associated marker that assists in the differential diagnosis of trophoblastic tumors and tumorlike lesions
The American Journal of Surgical Pathology, 2008Co-Authors: Robert J Kurman, Yungming Jeng, Wilber Huang, Ie Ming ShihAbstract:: Trophoblastic tumors and tumorlike lesions can be confused with a variety of nontrophoblastic tumors; therefore, a trophoblast-associated marker that is expressed in all types of trophoblastic lesions is useful in differential diagnosis. In this report, we assessed the potential of hydroxyl-delta-5-steroid dehydrogenase (HSD3B1), an enzyme that catalyzes the oxidative conversion of delta-5-3 beta-hydroxy steroids to the delta-4-3-keto configuration and that is involved in steroid hormone synthesis, as a diagnostic trophoblastic marker. First, the gene expression profile of HSD3B1 was analyzed in silica using serial analysis of gene expression in the database deposited in the public domain and found that HSD3B1 was not expressed in 159 libraries of breast, lung, colorectal, pancreatic, ovarian carcinomas, and a wide variety of normal adult and fetal tissues. Second, an immunohistochemical analysis was performed using a commercially available anti-HSD3B1 monoclonal antibody on paraffin sections. HSD3B1 immunoreactivity was detected in intermediate trophoblast and syncytiotrophoblast in 21 early placentas, 18 complete hydatidiform moles, 67 trophoblastic tumors, including placental site trophoblastic tumors, epithelioid trophoblastic tumors, and choriocarcinomas, and 28 tumorlike lesions including placental site nodules and exaggerated placental site. HSD3B1 immunoreactivity was diffuse and intense in the majority of trophoblastic lesions with the exception of a few choriocarcinomas. In contrast, only 3 (<1%) of 319 nontrophoblastic carcinomas from the uterus, lung, and breast reacted with the HSD3B1 antibody. Moreover, the immunoreactivity in these lesions was focal and weak. In conclusion, as compared with other trophoblastic markers, HSD3B1 is highly specific and sensitive, being expressed in all types of trophoblastic lesions but not in a variety of nontrophoblastic tumors of the uterus, lung, and breast.
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HSD3B1 as a novel trophoblast-associated marker that assists in the differential diagnosis of trophoblastic tumors and tumorlike lesions.
The American Journal of Surgical Pathology, 2008Co-Authors: Robert J Kurman, Yungming Jeng, Wilber Huang, Ie Ming ShihAbstract:Trophoblastic tumors and tumorlike lesions can be confused with a variety of nontrophoblastic tumors; therefore, a trophoblast-associated marker that is expressed in all types of trophoblastic lesions is useful in differential diagnosis. In this report, we assessed the potential of hydroxyl-6-5-steroid dehydrogenase (HSD3B1), an enzyme that catalyzes the oxidative conversion of δ-5-3 β-hydroxy steroids to the 8-4-3-keto configuration and that is involved in steroid hormone synthesis,14 as a diagnostic trophoblastic marker. First, the gene expression profile of HSD3B1 was analyzed in silica using serial analysis of gene expression in the database deposited in the public domain and found that HSD3B1 was not expressed in 159 libraries of breast, lung, colorectal, pancreatic, ovarian carcinomas, and a wide variety of normal adult and fetal tissues. Second, an immunohistochemical analysis was performed using a commercially available anti-HSD3B1 monoclonal antibody on paraffin sections. HSD3B1 immunoreactivity was detected in intermediate trophoblast and syncytiotrophoblast in 21 early placentas, 18 complete hydatidiform moles, 67 trophoblastic tumors, including placental site trophoblastic tumors, epithelioid trophoblastic tumors, and choriocarcinomas, and 28 tumorlike lesions including placental site nodules and exaggerated placental site. HSD3B1 immunoreactivity was diffuse and intense in the majority of trophoblastic lesions with the exception of a few choriocarcinomas. In contrast, only 3 (< 1%) of 319 nontrophoblastic carcinomas from the uterus, lung, and breast reacted with the HSD3B1 antibody. Moreover, the immunoreactivity in these lesions was focal and weak. In conclusion, as compared with other trophoblastic markers, HSD3B1 is highly specific and sensitive, being expressed in all types of trophoblastic lesions but not in a variety of nontrophoblastic tumors of the uterus, lung, and breast.
Hitoshi Okamura - One of the best experts on this subject based on the ideXlab platform.
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Clock genes and salt-sensitive hypertension: a new type of aldosterone-synthesizing enzyme controlled by the circadian clock and angiotensin II
Hypertension Research, 2016Co-Authors: Hitoshi Okamura, Kaoru Goto, Rika KojimaAbstract:With the current societal norm of shiftwork and long working hours, maintaining a stable daily life is becoming very difficult. An irregular lifestyle disrupts circadian rhythms, resulting in the malfunction of body physiology and ultimately leading to lifestyle-related diseases, including hypertension. By analyzing completely arrhythmic Cry1/Cry2 double-knockout ( Cry -null) mice, we found salt-sensitive hypertension accompanied by hyperaldosteronism. On the basis of a DNA microarray analysis of the adrenal gland and subsequent biochemical analyses, we discovered that Hsd3b6/HSD3B1, a subtype of 3β-HSD, is markedly overexpressed in aldosterone-producing cells in the Cry -null adrenal cortex. In addition, we found that Hsd3b6/HSD3B1, which converts pregnenolone to progesterone, is a clock-controlled gene and might also be a key enzyme for the regulation of aldosterone biosynthesis, in addition to the previously established CYP11B2, which synthesizes aldosterone from deoxycorticosterone. Importantly, angiotensin II induces HSD3B1 via the transcription factor NGFIB in human adrenocortical H295R cells, similarly to CYP11B2. As HSD3B1 levels are abnormally high in the adrenal aldosterone-producing cells of idiopathic hyperaldosteronism (IHA), the temporal component of this system in the pathophysiology of IHA is a promising area for future research.
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stimulus selective induction of the orphan nuclear receptor ngfib underlies different influences of angiotensin ii and potassium on the human adrenal gland zona glomerulosa specific 3β hsd isoform gene expression in adrenocortical h295r cells
Endocrine Journal, 2015Co-Authors: Daisuke Yarimizu, Hitoshi OkamuraAbstract:: In the adrenal, the type I 3β-hydroxysteroid dehydrogenase (HSD3B1) is expressed exclusively in the zona glomerulosa (ZG), where aldosterone is produced. Angiotensin II (AngII) and potassium (K(+)) are the major physiological regulators of aldosterone synthesis. However, their respective roles in regulation of aldosterone synthesis are not fully defined, particularly in terms of transcriptional regulation of steroidogenic enzyme genes. We previously showed that AngII can stimulate expression of HSD3B1. But, K(+) responsiveness of this gene has remained unexplored. Here, we report that K(+) stimulation lacks the ability to induce HSD3B1 expression in human adrenocortical H295R cells. Both AngII and K(+) were able to enhance transcription of the aldosterone synthase gene (CYP11B2). Promoter analysis revealed that although both AngII and K(+) activate transcription from the Ca(2+)/cAMP-responsive element (CRE) located in the CYP11B2 promoter, the orphan nuclear receptor NGFIB-responsive element (NBRE) located in the HSD3B1 promoter fails to respond to K(+), being only able to enhance transcription after AngII treatment. We found that induction of de novo protein synthesis of NGFIB occurs only after AngII treatment. This sharply contrasts with the phosphorylation that occurs in response to both AngII and K(+) on the CREB/ATF family transcription factor ATF2. Chromatin immunoprecipitation assay confirmed that the NGFIB protein occupies the HSD3B1 promoter only after AngII, while ATF2 binds to the CYP11B2 promoter in response to both AngII and K(+). These data provide evidence that downstream signals from AngII and K(+) can be uncoupled in the regulation of HSD3B1 in the human adrenocortical H295R cells.
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angiotensin ii triggers expression of the adrenal gland zona glomerulosa specific 3β hydroxysteroid dehydrogenase isoenzyme through de novo protein synthesis of the orphan nuclear receptors ngfib and nurr1
Molecular and Cellular Biology, 2014Co-Authors: Fumiyoshi Yamazaki, Daisuke Yarimizu, Kazuki Okada, Iori Murai, Hida Hayashi, Sumihiro Kunisue, Yuuki Nakagawa, Hitoshi OkamuraAbstract:The 3β-hydroxysteroid dehydrogenase (3β-HSD) is an enzyme crucial for steroid synthesis. Two different 3β-HSD isoforms exist in humans. Classically, HSD3B2 was considered the principal isoform present in the adrenal. However, we recently showed that the alternative isoform, HSD3B1, is expressed specifically within the adrenal zona glomerulosa (ZG), where aldosterone is produced, raising the question of why this isozyme needs to be expressed in this cell type. Here we show that in both human and mouse, expression of the ZG isoform 3β-HSD is rapidly induced upon angiotensin II (AngII) stimulation. AngII is the key peptide hormone regulating the capacity of aldosterone synthesis. Using the human adrenocortical H295R cells as a model system, we show that the ZG isoform HSD3B1 differs from HSD3B2 in the ability to respond to AngII. Mechanistically, the induction of HSD3B1 involves de novo protein synthesis of the nuclear orphan receptors NGFIB and NURR1. The HSD3B1 promoter contains a functional NGFIB/NURR1-responsive element to which these proteins bind in response to AngII. Knockdown of these proteins and overexpression of a dominant negative NGFIB both reduce the AngII responsiveness of HSD3B1. Thus, the AngII-NGFIB/NURR1 pathway controls HSD3B1. Our work reveals HSD3B1 as a new regulatory target of AngII.
Ie Ming Shih - One of the best experts on this subject based on the ideXlab platform.
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HSD3B1 as a novel trophoblast associated marker that assists in the differential diagnosis of trophoblastic tumors and tumorlike lesions
The American Journal of Surgical Pathology, 2008Co-Authors: Robert J Kurman, Yungming Jeng, Wilber Huang, Ie Ming ShihAbstract:: Trophoblastic tumors and tumorlike lesions can be confused with a variety of nontrophoblastic tumors; therefore, a trophoblast-associated marker that is expressed in all types of trophoblastic lesions is useful in differential diagnosis. In this report, we assessed the potential of hydroxyl-delta-5-steroid dehydrogenase (HSD3B1), an enzyme that catalyzes the oxidative conversion of delta-5-3 beta-hydroxy steroids to the delta-4-3-keto configuration and that is involved in steroid hormone synthesis, as a diagnostic trophoblastic marker. First, the gene expression profile of HSD3B1 was analyzed in silica using serial analysis of gene expression in the database deposited in the public domain and found that HSD3B1 was not expressed in 159 libraries of breast, lung, colorectal, pancreatic, ovarian carcinomas, and a wide variety of normal adult and fetal tissues. Second, an immunohistochemical analysis was performed using a commercially available anti-HSD3B1 monoclonal antibody on paraffin sections. HSD3B1 immunoreactivity was detected in intermediate trophoblast and syncytiotrophoblast in 21 early placentas, 18 complete hydatidiform moles, 67 trophoblastic tumors, including placental site trophoblastic tumors, epithelioid trophoblastic tumors, and choriocarcinomas, and 28 tumorlike lesions including placental site nodules and exaggerated placental site. HSD3B1 immunoreactivity was diffuse and intense in the majority of trophoblastic lesions with the exception of a few choriocarcinomas. In contrast, only 3 (<1%) of 319 nontrophoblastic carcinomas from the uterus, lung, and breast reacted with the HSD3B1 antibody. Moreover, the immunoreactivity in these lesions was focal and weak. In conclusion, as compared with other trophoblastic markers, HSD3B1 is highly specific and sensitive, being expressed in all types of trophoblastic lesions but not in a variety of nontrophoblastic tumors of the uterus, lung, and breast.
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HSD3B1 as a novel trophoblast-associated marker that assists in the differential diagnosis of trophoblastic tumors and tumorlike lesions.
The American Journal of Surgical Pathology, 2008Co-Authors: Robert J Kurman, Yungming Jeng, Wilber Huang, Ie Ming ShihAbstract:Trophoblastic tumors and tumorlike lesions can be confused with a variety of nontrophoblastic tumors; therefore, a trophoblast-associated marker that is expressed in all types of trophoblastic lesions is useful in differential diagnosis. In this report, we assessed the potential of hydroxyl-6-5-steroid dehydrogenase (HSD3B1), an enzyme that catalyzes the oxidative conversion of δ-5-3 β-hydroxy steroids to the 8-4-3-keto configuration and that is involved in steroid hormone synthesis,14 as a diagnostic trophoblastic marker. First, the gene expression profile of HSD3B1 was analyzed in silica using serial analysis of gene expression in the database deposited in the public domain and found that HSD3B1 was not expressed in 159 libraries of breast, lung, colorectal, pancreatic, ovarian carcinomas, and a wide variety of normal adult and fetal tissues. Second, an immunohistochemical analysis was performed using a commercially available anti-HSD3B1 monoclonal antibody on paraffin sections. HSD3B1 immunoreactivity was detected in intermediate trophoblast and syncytiotrophoblast in 21 early placentas, 18 complete hydatidiform moles, 67 trophoblastic tumors, including placental site trophoblastic tumors, epithelioid trophoblastic tumors, and choriocarcinomas, and 28 tumorlike lesions including placental site nodules and exaggerated placental site. HSD3B1 immunoreactivity was diffuse and intense in the majority of trophoblastic lesions with the exception of a few choriocarcinomas. In contrast, only 3 (< 1%) of 319 nontrophoblastic carcinomas from the uterus, lung, and breast reacted with the HSD3B1 antibody. Moreover, the immunoreactivity in these lesions was focal and weak. In conclusion, as compared with other trophoblastic markers, HSD3B1 is highly specific and sensitive, being expressed in all types of trophoblastic lesions but not in a variety of nontrophoblastic tumors of the uterus, lung, and breast.
Yuhyu Chou - One of the best experts on this subject based on the ideXlab platform.
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HSD3B1 is a specific trophoblast associated marker not expressed in a wide spectrum of tumors
International Journal of Gynecological Cancer, 2013Co-Authors: Yuhyu Chou, Yungming JengAbstract:Objective Hydroxyl-δ-5-steroid dehydrogenase (HSD3B1) is an enzyme that catalyzes the oxidative conversion of δ-5-3 β-hydroxyl steroids to the δ-4-3-keto configuration and is involved in steroid hormone synthesis. It has been shown to be expressed in normal trophoblastic tissue and benign and neoplastic trophoblastic lesions. HSD3B1 has not been detected in a large number of lung, breast, and uterine carcinomas; however, its expression has not been studied in a wide variety of other nontrophoblastic neoplasms. To test if HSD3B1 is highly specific for normal trophoblasts and trophoblast-associated lesions, we examined the expression of HSD3B1 in a wide spectrum of tumors. Methods Tissue microarrays containing 473 carcinomas from the lung, breast, ovary, uterus, liver, pancreas, stomach, and colon; 32 ovarian granulose cell tumors; and 12 adrenocortical adenomas were studied by immunohistochemistry using a commercially available monoclonal antibody, HSD3B1. One tissue microarray containing normal tissues was also included. Positive staining of intermediate trophoblasts and syncytiotrophoblasts in normal placental tissue served as a positive control. Results Normal tissues and tumors from the various sites were all negative for HSD3B1 except for 2 adrenocortical adenomas with weak focal immunoreactivity. Conclusions Our study further confirmed that HSD3B1 is a highly specific trophoblast-associated marker that can be used in the distinction of trophoblastic tumorlike lesions and tumors from nontrophoblastic lesions and tumors.