HSD3B1

Gene Summary

Gene:HSD3B1; hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1
Aliases: I, HSD3B, HSDB3, HSDB3A, SDR11E1, 3BETAHSD
Location:1p13.1
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Prostate-Specific Antigen
  • Glucuronosyltransferase
  • Gene Expression
  • Uterine Cancer
  • Hydroxysteroid Dehydrogenases
  • Xeroderma Pigmentosum Group D Protein
  • Gonadal Steroid Hormones
  • Disease Progression
  • Messenger RNA
  • Estrogens
  • Genetic Variation
  • Chromosome 1
  • Phosphoproteins
  • Stomach Cancer
  • CYP17
  • Testosterone
  • Risk Factors
  • Dihydrotestosterone
  • Cholesterol Side-Chain Cleavage Enzyme
  • Cancer Gene Expression Regulation
  • Aromatase
  • 3-Hydroxysteroid Dehydrogenases
  • Single Nucleotide Polymorphism
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • Progesterone Reductase
  • Genotype
  • Sulfotransferases
  • Multienzyme Complexes
  • Pregnancy
  • Estradiol Dehydrogenases
  • Polymorphism
  • Androgens
  • Enzymologic Gene Expression Regulation
  • Genetic Predisposition
  • Prostate Cancer
  • Tumor Markers
  • Polymerase Chain Reaction
  • Steroid Isomerases
  • Androstenedione
  • DNA-Binding Proteins
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HSD3B1 (cancer-related)

Wu G, Huang S, Nastiuk KL, et al.
Variant allele of HSD3B1 increases progression to castration-resistant prostate cancer.
Prostate. 2015; 75(7):777-82 [PubMed] Related Publications
BACKGROUND: 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which is a rate-limiting enzyme that catalyzes the conversion of adrenal-derived steroid dehydroepiandrosterone to dihydrotestosterone (DHT), may be a promising target for treating castration-resistant prostate cancer (CRPC).
METHODS: From 2004 to 2011, a total of 103 consecutive patients presenting with advanced prostate cancer were included in this study. All patients were treated with surgical castration as androgen-deprivation therapy (ADT). Germline DNA was extracted from archived tissue from each patient and sequenced. PSA half-time (representing rate to PSA nadir after ADT), the incidence of, and time to CRPC occurrence, and cause-specific mortality rates were determined during the 3-10 years follow-up. The perioperative data and postoperative outcomes are compared. The patients were retrospectively analyzed for survival time.
RESULTS: Of the 103 patient samples analyzed, 18 harbored a heterozygous variant (1245C) HSD3B1 gene, while 85 patients were homozygous wild-type (1245A) for HSD3B1. The two groups were homogenous for age, PSA, Gleason and metastases rate preoperatively. The incidence of CRPC observed in the variant group was significantly higher than that of wild-type group (100% vs. 64.7%, respectively; P = 0.003). Despite this higher incidence of CRPC, there were no significant differences in time to develop CRPC, or in cause-specific mortality. Further, neither PSA half-time, nor time to biochemical recurrence were different between the variant and wild-type groups.
CONCLUSION: Prostate cancer patients who harbored the heterozygous variant HSD3B1 (1245C) are more likely to develop to CRPC, but do not have shorter time to biochemical recurrence, shorter survival time or higher mortality risk.

Lottrup G, Nielsen JE, Skakkebæk NE, et al.
Abundance of DLK1, differential expression of CYP11B1, CYP21A2 and MC2R, and lack of INSL3 distinguish testicular adrenal rest tumours from Leydig cell tumours.
Eur J Endocrinol. 2015; 172(4):491-9 [PubMed] Related Publications
OBJECTIVE: Testicular adrenal rest tumours (TARTs) are a common finding in patients with congenital adrenal hyperplasia (CAH). These tumours constitute a diagnostic and management conundrum and may lead to infertility. TART cells share many functional and morphological similarities with Leydig cells (LCs), and masses consisting of such cells are occasionally misclassified as malignant testicular tumours, which may lead to erroneous orchiectomy in these patients.
DESIGN: In this study, we aimed to investigate the potential of LC developmental markers and adrenal steroidogenic markers in the differential diagnosis of TARTs and malignant LC tumours (LCTs).
METHODS: We investigated mRNA and protein expression of testicular steroidogenic enzymes; CYP11A1 and HSD3B1/2, markers of adrenal steroidogenesis; CYP11B1, CYP21A2 and ACTH receptor/melanocortin 2 receptor (MC2R), and markers of LC maturation; and delta-like 1 homolog (DLK1) and insulin-like 3 (INSL3) in testicular biopsies with TART, orchiectomy specimens with LCTs and samples from human fetal adrenals.
RESULTS: Expression of testicular steroidogenic enzymes was observed in all specimens. All investigated adrenal steroidogenic markers were expressed in TART, and weak reactions for CYP11B1 and MC2R were observed at the protein level in LTCs. TART and fetal adrenals had identical expression profiles. DLK1 was highly expressed and INSL3 not detectable in TART, whereas INSL3 was highly expressed in LCTs.
CONCLUSIONS: The similar expression profiles in TART and fetal adrenals as well as the presence of classical markers of adrenal steroidogenesis lend support to the hypothesis that TART develops from a displaced adrenal cell type. Malignant LCTs seem to have lost DLK1 expression and do not resemble immature LCs. The different expression pattern of DLK1, INSL3 and most adrenocortical markers adds to the elucidation of the histogenesis of testicular interstitial tumours and may facilitate histopathological diagnosis.

Hogg K, Robinson WP, Beristain AG
Activation of endocrine-related gene expression in placental choriocarcinoma cell lines following DNA methylation knock-down.
Mol Hum Reprod. 2014; 20(7):677-89 [PubMed] Related Publications
Increasingly, placental DNA methylation is assessed as a factor in pregnancy-related complications, yet the transcriptional impact of such findings is not always clear. Using a proliferative in vitro placental model, the effect of DNA methylation loss on gene activation was evaluated at a number of genes selected for being differentially methylated in pre-eclampsia-associated placentae in vivo. We aimed to determine whether reduced DNA methylation at specific loci was associated with transcriptional changes at the corresponding gene, thus providing mechanistic underpinnings for previous clinical findings and to assess the degree of transcriptional response amongst our candidate genes. BeWo and JEG3 choriocarcinoma cells were exposed to 1 μM 5-Aza-2'-deoxycytidine (5-Aza-CdR) or vehicle control for 48 h, and re-plated and cultured for a further 72 h in normal media before cells were harvested for RNA and DNA. Bisulphite pyrosequencing confirmed that DNA methylation was reduced by ∼30-50% points at the selected loci studied in both cell lines. Gene activation, measured by qRT-PCR, was highly variable and transcript specific, indicating differential sensitivity to DNA methylation. Most notably, loss of DNA methylation at the leptin (LEP) promoter corresponded to a 200-fold and 40-fold increase in LEP expression in BeWo and JEG3 cells, respectively (P < 0.01). Transcripts of steroidogenic pathway enzymes CYP11A1 and HSD3B1 were up-regulated ∼40-fold in response to 5-Aza-CdR exposure in BeWo cells (P < 0.01). Other transcripts, including aromatase (CYP19), HSD11B2, inhibin (INHBA) and glucocorticoid receptor (NR3C1) were more moderately, although significantly, affected by loss of associated DNA methylation. These data present a mixed effect of DNA methylation changes at selected loci supporting cautionary interpretation of DNA methylation results in the absence of functional data.

Hanamura T, Niwa T, Gohno T, et al.
Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers.
Breast Cancer Res Treat. 2014; 143(1):69-80 [PubMed] Related Publications
Aromatase inhibitors (AIs) exert antiproliferative effects by reducing local estrogen production from androgens in postmenopausal women with hormone-responsive breast cancer. Previous reports have shown that androgen metabolites generated by the aromatase-independent enzymes, 5α-androstane-3β, 17β-diol (3β-diol), androst-5-ene-3β, and 17β-diol (A-diol), also activate estrogen receptor (ER) α. Estradiol (E2) can also reportedly be generated from estrone sulfate (E1S) pooled in the plasma. Estrogenic steroid-producing aromatase-independent pathways have thus been proposed as a mechanism of AI resistance. However, it is unclear whether these pathways are functional in clinical breast cancer. To investigate this issue, we assessed the transcriptional activities of ER in 45 ER-positive human breast cancers using the adenovirus estrogen-response element-green fluorescent protein assay and mRNA expression levels of the ER target gene, progesterone receptor, as indicators of ex vivo and in vivo ER activity, respectively. We also determined mRNA expression levels of 5α-reductase type 1 (SRD5A1) and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD type 1; HSD3B1), which produce 3β-diol from androgens, and of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD type 1; HSD17B1), which produce E2 or A-diol from E1S or dehydroepiandrosterone sulfate. SRD5A1 and HSD3B1 expression levels were positively correlated with ex vivo and in vivo ER activities. STS and HSD17B1 expression levels were positively correlated with in vivo ER activity alone. Elevated expression levels of these steroid-metabolizing enzymes in association with high in vivo ER activity were particularly notable in postmenopausal patients. Analysis of the expression levels of steroid-metabolizing enzymes revealed positive correlations between SRD5A1 and HSD3B1, and STS and HSD17B1. These findings suggest that the SRD5A1-HSD3B1 as well as the STS-HSD17B pathways, could contributes to ER activation, especially postmenopause. These pathways might function as an alternative estrogenic steroid-producing, aromatase-independent pathways.

Szabó DR, Baghy K, Szabó PM, et al.
Antitumoral effects of 9-cis retinoic acid in adrenocortical cancer.
Cell Mol Life Sci. 2014; 71(5):917-32 [PubMed] Related Publications
The currently available medical treatment options of adrenocortical cancer (ACC) are limited. In our previous meta-analysis of adrenocortical tumor genomics data, ACC was associated with reduced retinoic acid production and retinoid X receptor-mediated signaling. Our objective has been to study the potential antitumoral effects of 9-cis retinoic acid (9-cisRA) on the ACC cell line NCI-H295R and in a xenograft model. Cell proliferation, hormone secretion, and gene expression have been studied in the NCI-H295R cell line. A complex bioinformatics approach involving pathway and network analysis has been performed. Selected genes have been validated by real-time qRT-PCR. Athymic nude mice xenografted with NCI-H295R have been used in a pilot in vivo xenograft model. 9-cisRA significantly decreased cell viability and steroid hormone secretion in a concentration- and time-dependent manner in the NCI-H295R cell line. Four major molecular pathways have been identified by the analysis of gene expression data. Ten genes have been successfully validated involved in: (1) steroid hormone secretion (HSD3B1, HSD3B2), (2) retinoic acid signaling (ABCA1, ABCG1, HMGCR), (3) cell-cycle damage (GADD45A, CCNE2, UHRF1), and the (4) immune response (MAP2K6, IL1R2). 9-cisRA appears to directly regulate the cell cycle by network analysis. 9-cisRA also reduced tumor growth in the in vivo xenograft model. In conclusion, 9-cisRA might represent a promising new candidate in the treatment of hormone-secreting adrenal tumors and adrenocortical cancer.

Hanamura T, Niwa T, Nishikawa S, et al.
Androgen metabolite-dependent growth of hormone receptor-positive breast cancer as a possible aromatase inhibitor-resistance mechanism.
Breast Cancer Res Treat. 2013; 139(3):731-40 [PubMed] Related Publications
Aromatase inhibitors (AIs) have been reported to exert their antiproliferative effects in postmenopausal women with hormone receptor-positive breast cancer not only by reducing estrogen production but also by unmasking the inhibitory effects of androgens such as testosterone (TS) and dihydrotestosterone (DHT). However, the role of androgens in AI-resistance mechanisms is not sufficiently understood. 5α-Androstane-3β,17β-diol (3β-diol) generated from DHT by 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) shows androgenic and substantial estrogenic activities, representing a potential mechanism of AI resistance. Estrogen response element (ERE)-green fluorescent protein (GFP)-transfected MCF-7 breast cancer cells (E10 cells) were cultured for 3 months under steroid-depleted, TS-supplemented conditions. Among the surviving cells, two stable variants showing androgen metabolite-dependent ER activity were selected by monitoring GFP expression. We investigated the process of adaptation to androgen-abundant conditions and the role of androgens in AI-resistance mechanisms in these variant cell lines. The variant cell lines showed increased growth and induction of estrogen-responsive genes rather than androgen-responsive genes after stimulation with androgens or 3β-diol. Further analysis suggested that increased expression of HSD3B1 and reduced expression of androgen receptor (AR) promoted adaptation to androgen-abundant conditions, as indicated by the increased conversion of DHT into 3β-diol by HSD3B1 and AR signal reduction. Furthermore, in parental E10 cells, ectopic expression of HSD3B1 or inhibition of AR resulted in adaptation to androgen-abundant conditions. Coculture with stromal cells to mimic local estrogen production from androgens reduced cell sensitivity to AIs compared with parental E10 cells. These results suggest that increased expression of HSD3B1 and reduced expression of AR might reduce the sensitivity to AIs as demonstrated by enhanced androgen metabolite-induced ER activation and growth mechanisms. Androgen metabolite-dependent growth of breast cancer cells may therefore play a role in AI-resistance.

Huuskonen P, Myllynen P, Storvik M, Pasanen M
The effects of aflatoxin B1 on transporters and steroid metabolizing enzymes in JEG-3 cells.
Toxicol Lett. 2013; 218(3):200-6 [PubMed] Related Publications
Effects of 96 h aflatoxin B1 (AFB1) exposure at concentrations from 0.2 μM to 6 μM on the mRNA and protein expression levels of the following transporters ABCB1/B4, ABCC1, ABCC2, ABCG2, OAT4 and the mRNA expression of steroid-metabolizing enzymes CYP1A1, CYP19A1, HSD3B1 and HSD17B1, and conjugating enzyme family UGT1A were evaluated in trophoblastic JEG-3 cells. Statistically significant dose-dependent five-fold increases in the expression levels with ABCC2 and OAT4 were recorded at 2 and 6μM AFB1. Protein expression of ABCG2 was decreased dose-dependently with 0.2-6 μM AFB1. With the other transporters, only a trend of increased expression was observed. Analogously, a three-fold increase in the expressions of CYP19A1, HSD3B1, HSD17B1 and UGT1A-family were observed at 0.3 μM AFB1. When an inhibitor of CYP19A1, finrozole, was dosed simultaneously with AFB1, no increases in the transcripts of transporters or steroid hydroxylases or CYP19A1 were observed. This delayed increase in the expression levels - only after 96h incubations - may indicate that the response is due to a secondary metabolite of AFB1 or other secondary controlling cascades rather than the parent compound itself. In conclusion, AFB1 affected the placental steroid synthesizing, metabolizing and conjugating enzymes as well as the expression levels of several transporter proteins in JEG-3 cells. These alterations may lead to anomalies in the foetoplacental hormonal homeostasis.

Andrew AS, Hu T, Gu J, et al.
HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.
PLoS One. 2012; 7(12):e51301 [PubMed] Free Access to Full Article Related Publications
Bladder cancer is the 4(th) most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25) than females (OR 1.56 95%CI 0.83-2.95), (SNP-gender interaction P = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003). The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.

Arai S, Shibata Y, Nakamura Y, et al.
Development of prostate cancer in a patient with primary hypogonadism: intratumoural steroidogenesis in prostate cancer tissues.
Andrology. 2013; 1(1):169-74 [PubMed] Related Publications
Intratumoural steroidogenesis may play a significant role in the progression of prostate cancer (PC) in the context of long-term ablation of circulating testosterone (T). To clarify the mechanism accounting for the progression of PC in a 74-year-old man who had undergone bilateral orchiectomy when he was 5 years old, we performed immunohistochemical studies of androgen receptor (AR) and steroidogenic enzymes in the prostate. We also measured steroid hormone levels in the serum and prostate, as well as mRNA levels of genes mediating androgen metabolism in the prostate. Positive nuclear staining of AR was detected in malignant epithelial cells. The levels of androstenedione (Adione), T, and 5-alpha dihydrotestosterone (DHT) in the serum of the patient were similar to those in PC patients receiving neoadjuvant androgen deprivation therapy (ADT), but were higher in the patient's prostate than in PC patients not receiving ADT. The gene expression of CYP17A1 and HSD3B1 was not detected, whereas that of STS, HSD3B2, AKR1C3, SRD5A1, and SRD5A2 was detected. Moreover, cytoplasmic staining of HSD3B2, AKR1C3, SRD5A1, and SRD5A2 was detected in malignant epithelial cells. Hence, in the present case (a man with primary hypogonadism), steroidogenesis in PC tissues from adrenal androgens, especially dehydroepiandrosterone sulphate, was the mechanism accounting for progression of PC. This mechanism might help elucidate the development of castration-resistant PC.

Sinreih M, Hevir N, Rižner TL
Altered expression of genes involved in progesterone biosynthesis, metabolism and action in endometrial cancer.
Chem Biol Interact. 2013; 202(1-3):210-7 [PubMed] Related Publications
Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. It is associated with prolonged exposure to estrogens that is unopposed by the protective effects of progesterone, which suggests that altered progesterone biosynthesis, metabolism and actions might be implicated in the development of EC. Our aim was to evaluate these processes through quantitative real-time PCR expression analysis in up to 47 pairs of EC tissue and adjacent control endometrium. First, we examined the expression of genes encoding proteins associated with progesterone biosynthesis: steroidogenic acute regulatory protein (STAR); a side chain cleavage enzyme (CYP11A1); and 3β-hydroxysteroid dehydrogenase/ketosteroid isomerase (HSD3B). There were 1.9- and 10.0-fold decreased expression of STAR and CYP11A1, respectively, in EC versus adjacent control endometrium, with no significant differences in the expression of HSD3B1 and HSD3B2. Next, we examined expression of genes encoding five progesterone metabolizing enzymes: the 3-keto and 20-ketosteroid reductases (AKR1C1-AKR1C3) and 5α-reductases (SRD5A1 and SRD5A2); and the opposing 20α-hydroxysteroid dehydrogenase (HSD17B2). These genes are expressed in EC and adjacent control endometrium. No statistically significant differences were seen in mRNA levels of AKR1C1, AKR1C2, AKR1C3 and SRD5A1. Expression of HSD17B2 was 3.0-fold increased, and expression of SRD5A2 was 3.7-fold decreased, in EC versus adjacent control endometrium. We also examined mRNA levels of progesterone receptors A and B (PGR), and separately the expression of progesterone receptor B (PR-B). Here we saw 1.8- and 2.0-fold lower mRNA levels of PGR and PR-B, respectively, in EC versus adjacent control endometrium. This down-regulation of STAR, CYP11A1 and PGR in endometrial cancer may lead to decreased progesterone biosynthesis and actions although the effects on progesterone levels should be further studied.

Lévesque É, Huang SP, Audet-Walsh É, et al.
Molecular markers in key steroidogenic pathways, circulating steroid levels, and prostate cancer progression.
Clin Cancer Res. 2013; 19(3):699-709 [PubMed] Related Publications
PURPOSE: Prostate cancer is a heterogeneous genetic disease, and molecular methods for predicting prognosis in patients with aggressive form of the disease are urgently needed to better personalize treatment approaches. The objective was to identify host genetic variations in candidate steroidogenic genes affecting hormone levels and prostate cancer progression.
EXPERIMENTAL DESIGN: The study examined two independent cohorts composed of 526 Caucasian men with organ-confined prostate cancer and 601 Taiwanese men on androgen-deprivation therapy. Caucasians were genotyped for 109 haplotype-tagging single-nucleotide polymorphisms (SNP) in CYP17A1, ESR1, CYP19A1, and HSD3B1, and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings, including previously identified SRD5A1, SRD5A2, HSD17B2, HSD17B3, and HSD17B12 polymorphisms, were then explored in Taiwanese men (n = 32 SNPs). The influence of positive markers on the circulating hormonal levels was then appraised in Caucasians using specific and sensitive mass spectrometry-based methods.
RESULTS: After adjusting for known risk factors, variants of CYP17A1 (rs6162), HSD17B2 (rs4243229 and rs7201637), and ESR1 (rs1062577) were associated with progressive disease in both cohorts. Indeed, the presence of these variations was significantly associated with progression in Caucasians (HR, 2.29-4.10; P = 0.0014-2 × 10(-7)) and survival in Taiwanese patients [HR = 3.74; 95% confidence interval (CI): 1.71-8.19, P = 0.009]. Remarkably, the CYP17A1 rs6162 polymorphism was linked to plasma dehydroepiandrosterone-sulfate (DHEA-S) levels (P = 0.03), HSD17B2 rs7201637 with levels of dihydrotestosterone (P = 0.03), and ESR1 rs1062577 with levels of estrone-S and androsterone-glucuronide (P ≤ 0.05).
CONCLUSION: This study identifies, in different ethnic groups and at different disease stages, CYP17A1, HSD17B2, and ESR1 as attractive prognostic molecular markers of prostate cancer progression.

Lichtenauer UD, Shapiro I, Osswald A, et al.
Characterization of NCI-H295R cells as an in vitro model of hyperaldosteronism.
Horm Metab Res. 2013; 45(2):124-9 [PubMed] Related Publications
In depth analysis of key molecular mechanisms involved in functional autonomy of aldosterone secretion is hampered by the lack of tumor cell lines that reflect functional characteristics of aldosterone producing adenomas. Herein, we describe the characteristics of the adrenocortical carcinoma cell line NCI-H295R and its suitability as a model of hyperaldosteronism in relation to different culture conditions. Steroid profiling revealed that NCI-H295R cells predominantly secrete cortisol, while aldosterone and other steroids are released at much lower concentrations. However, aldosterone output specifically increased in response to different stimuli such as ACTH and angiotensin II, and in particular to potassium in a dose dependent manner. NCI-H295R cells readily formed spheroids under specific culture conditions, a method widely used for the enrichment of progenitor cells. Unexpectedly, spheroid cells excelled with higher aldosterone concentration and higher expression levels of the steroidogenic enzymes StAR, 3βHSD, CYP17, SF-1, and the MC2-receptor. Further investigations revealed that this phenomenon is mainly attributed to epithelial growth factor (EGF) and particularly fibroblast growth factor (FGF), which are both essential ingredients in the spheroid culture medium. Aldosterone release under the combinatory influence of EGF and FGF was not higher than the effect of FGF alone. Spheroid growth per se, therefore, does not ensure an enrichment of less differentiated cell types in this cell line.

Cho LY, Yang JJ, Ko KP, et al.
Genetic susceptibility factors on genes involved in the steroid hormone biosynthesis pathway and progesterone receptor for gastric cancer risk.
PLoS One. 2012; 7(10):e47603 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The objective of the study was to investigate the role of genes (HSD3B1, CYP17A1, CYP19A1, HSD17B2, HSD17B1) involved in the steroid hormone biosynthesis pathway and progesterone receptor (PGR) in the etiology of gastric cancer in a population-based two-phase genetic association study.
METHODS: In the discovery phase, 108 candidate SNPs in the steroid hormone biosynthesis pathway related genes and PGR were analyzed in 76 gastric cancer cases and 322 controls in the Korean Multi-Center Cancer Cohort. Statistically significant SNPs identified in the discovery phase were re-evaluated in an extended set of 386 cases and 348 controls. Pooled- and meta-analyses were conducted to summarize the results.
RESULTS: Of the 108 SNPs in steroid hormone biosynthesis pathway related genes and PGR analyzed in the discovery phase, 23 SNPs in PGR in the recessive model and 10 SNPs in CYP19A1 in the recessive or additive models were significantly associated with increased gastric cancer risk (p<0.05). The minor allele frequencies of the SNPs in both the discovery and extension phases were not statistically different. Pooled- and meta-analyses showed CYP19A1 rs1004982, rs16964228, and rs1902580 had an increased risk for gastric cancer (pooled OR [95% CI] = 1.22 [1.01-1.48], 1.31 [1.03-1.66], 3.03 [1.12-8.18], respectively). In contrast, all PGR SNPs were not statistically significantly associated with gastric cancer risk.
CONCLUSIONS: Our findings suggest CYP19A1 that codes aromatase may play an important role in the association of gastric cancer risk and be a genetic marker for gastric cancer susceptibility.

Zsippai A, Szabó DR, Tömböl Z, et al.
Effects of mitotane on gene expression in the adrenocortical cell line NCI-H295R: a microarray study.
Pharmacogenomics. 2012; 13(12):1351-61 [PubMed] Related Publications
AIM: The adrenolytic agent mitotane is widely used in the treatment of adrenocortical cancer; however, its mechanism of action is poorly elucidated. We have studied mitotane-induced mRNA expression changes in the NCI-H295R adrenocortical cancer cell line.
MATERIALS & METHODS: Cell viability and hormone assays were used to select the optimal mitotane concentration effectively inhibiting hormone secretion without affecting cell viability. RNA isolated from cultures treated for 48 and 72 h was subjected to Agilent 4×44K microarray platforms. Microarray results were validated by quantitative reverse-transcription PCR.
RESULTS: Altogether, 117 significantly differentially expressed genes were detected at 48 h and 72 h (p < 0.05) in mitotane-treated samples relative to controls. Three significantly underexpressed genes involved in steroid hormone biosynthesis (HSD3B1, HSD3B2 and CYP21A2) and four significantly overexpressed genes (GDF15, ALDH1L2, TRIB3 and SERPINE2) have been validated.
CONCLUSION: Gene-expression changes might be involved in the adrenal action of mitotane and in the inhibition of hormone secretion.

Li R, Evaul K, Sharma KK, et al.
Abiraterone inhibits 3β-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer.
Clin Cancer Res. 2012; 18(13):3571-9 [PubMed] Related Publications
PURPOSE: Treatment with abiraterone (abi) acetate prolongs survival in castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to upregulation of steroidogenic enzymes and/or other mechanisms that sustain dihydrotestosterone (DHT) synthesis, which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. On the basis of the 3β-hydroxyl, Δ(5)-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for DHT synthesis in CRPC, regardless of origins or routes of synthesis.
EXPERIMENTAL DESIGN: We tested the effects of abi on 3βHSD activity, androgen receptor localization, expression of androgen receptor-responsive genes, and CRPC growth in vivo.
RESULTS: Abi inhibits recombinant 3βHSD activity in vitro and endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [(3)H]-dehydroepiandrosterone (DHEA) to Δ(4)-androstenedione, androgen receptor nuclear translocation, expression of androgen receptor-responsive genes, and xenograft growth in orchiectomized mice supplemented with DHEA. Abi also blocks conversion of Δ(5)-androstenediol to testosterone by 3βHSD. Abi inhibits 3βHSD1 and 3βHSD2 enzymatic activity in vitro; blocks conversion from DHEA to androstenedione and DHT with an IC(50) value of less than 1 μmol/L in CRPC cell lines; inhibits androgen receptor nuclear translocation; expression of TMPRSS2, prostate-specific antigen, and FKBP5; and decreases CRPC xenograft growth in DHEA-supplemented mice.
CONCLUSIONS: We conclude that abi inhibits 3βHSD-mediated conversion of DHEA to active androgens in CRPC. This second mode of action might be exploited to reverse resistance to CYP17A1 inhibition at the standard abi dose by dose-escalation or simply by administration with food to increase drug exposure.

Dumas I, Diorio C
Estrogen pathway polymorphisms and mammographic density.
Anticancer Res. 2011; 31(12):4369-86 [PubMed] Related Publications
Elevated mammographic density (MD) is strongly associated with breast cancer risk and the estrogen pathway has been proposed as a potential mechanism for this association. It has been repeatedly observed that several established estrogen-related factors associated with breast cancer risk, such as parity and hormone replacement therapy, are also associated with MD. However, the association of circulating estrogen levels (known to be strongly positively associated with breast cancer risk) with MD has so far been inconsistent. Since MD is highly heritable, single nucleotide polymorphisms (SNPs) in genes involved in the estrogen pathway and their relation with MD could provide information that would help understand the link between MD and breast cancer risk. This review of 18 studies describes the relation of SNPs located in genes of the estrogen pathway (genes coding for hydroxysteroid dehydrogenases (HSD3B1, HSD17B1), cytochrome P450 (CYP1A1, CYP1A2, CYP17A1, CYP19A1 and CYP1B1), catechol-O-methyltransferase (COMT), uridine diphospho-glucuronosyltransferase (UGT1A1), sulfotransferases (SULT1A1, SULT1E1) and for estrogen receptors alpha and beta (ESR1, ESR2)) with MD. Most of the SNPs evaluated showed no association with MD when analyses were performed on overall study population. However, when this relation was assessed within strata based on estrogen-related factors, a few SNPs (HSD17B1 (rs2010750, rs598126 and rs676387), COMT (rs4680), UGT1A1 (rs8175347) and ESR1 (rs9340799)) seemed to be related to MD in the same direction of their associations with breast cancer risk. Since such data are very limited, additional research including stratified analyses by factors related to estrogen are needed to validate these findings.

Hogg K, Young JM, Oliver EM, et al.
Enhanced thecal androgen production is prenatally programmed in an ovine model of polycystic ovary syndrome.
Endocrinology. 2012; 153(1):450-61 [PubMed] Related Publications
One of the hallmarks of polycystic ovary syndrome (PCOS) is increased ovarian androgen secretion that contributes to the ovarian, hormonal, and metabolic features of this condition. Thecal cells from women with PCOS have an enhanced capacity for androgen synthesis. To investigate whether this propensity is a potential cause, rather than a consequence, of PCOS, we used an ovine prenatal androgenization model of PCOS and assessed ewes at 11 months of age. Pregnant Scottish Greyface ewes were administered 100 mg testosterone propionate (TP) or vehicle control twice weekly from d 62 to 102 of gestation, and female offspring (TP = 9, control = 5) were studied. Prenatal TP exposure did not alter ovarian morphology or cyclicity, or plasma androgen, estrogen, and gonadotropin concentrations, at this stage. However, follicle function was reprogrammed in vivo with increased proportions of estrogenic follicles (P < 0.05) in the TP-exposed cohort. Furthermore, in vitro the thecal cells of follicles (>4 mm) secreted more LH-stimulated androstenedione after prenatal androgenization (P < 0.05), associated with increased basal expression of thecal StAR (P < 0.01), CYP11A (P < 0.05), HSD3B1 (P < 0.01), CYP17 (P < 0.05), and LHR (P < 0.05). This provides the first evidence of increased thecal androgenic capacity in the absence of a PCOS phenotype, suggesting a thecal defect induced during fetal life.

Pinski J, Xiong S, Wang Q, et al.
Effect of luteinizing hormone on the steroidogenic pathway in prostate cancer.
Prostate. 2011; 71(8):892-8 [PubMed] Related Publications
BACKGROUND: Recent data has shown that prostate cancer (PCA) cells are capable of producing testosterone directly from cholesterol, which may contribute to the development of castration resistance. While up-regulation of steroidogenic enzymes has been previously described during castration-resistant prostate cancer (CRPC) progression, regulation of this process is poorly defined. These data examine the role of luteinizing hormone (LH) in the regulation of steroidogenic machinery in PCA cells.
METHODS: PCA cell lines LNCaP, C4-2B, and 22RV1 were exposed to LH. Gene expression was quantified using real-time PCR and protein expression was characterized with standard Western blot analysis. Steroid analysis was performed using radioimmunoassay (RIA). Cell viability was measured using an MTS viability assay.
RESULTS: Androgen-sensitive (LNCaP) and -independent PCA cells (C4-2B and 22RV1) express both mRNA and protein for LH and LH receptor (LHR). Exposure of these cells to LH for 4 hr increased the expression of several steroidogenic genes. Exposure for 10 days resulted in the increase of additional genes. At both time points, the upregulation of these genes was dose-dependent. This was mirrored by an increase in the expression of several key steroidogenic enzymes, including StAR, CYB5B, CYP11A, and 3βHSD. LH stimulated the production of progesterone and testosterone in LNCaP cells as measured by RIA. We have also demonstrated that treatment of LNCaP cells with LH enhanced their viability.
CONCLUSIONS: Our data show that LH-mediated activation of LHR significantly up-regulates the expression of genes and enzymes required for steroidogenesis and increases steroid production in PCA cells.

Ji K, Choi K, Lee S, et al.
Effects of sulfathiazole, oxytetracycline and chlortetracycline on steroidogenesis in the human adrenocarcinoma (H295R) cell line and freshwater fish Oryzias latipes.
J Hazard Mater. 2010; 182(1-3):494-502 [PubMed] Related Publications
Pharmaceuticals in the environment are of growing concern for their potential consequences on human and ecosystem health. Alterations in the endocrine system in humans or wildlife are of special interest because these alterations could eventually lead to changes in reproductive fitness. Using the H295R cell line, the potential endocrine disrupting effects of six pharmaceuticals including diclofenac, erythromycin, sulfamethazine, sulfathiazole, oxytetracycline, and chlortetracycline were investigated. After exposure to each target pharmaceutical for 48 h, production of 17beta-estradiol (E2) and testosterone (T), aromatase (CYP19) enzyme activity, or expression of steroidogenic genes were measured. Concentrations of E2 in blood plasma were determined in male Japanese medaka fish after 14 d exposure to sulfathiazole, oxytetracycline, or chlortetracycline. Among the pharmaceuticals studied, sulfathiazole, oxytetracycline and chlortetracycline all significantly affected E2 production by H295R cells. This mechanism of the effect was enhanced aromatase activity and up-regulation of mRNAs for CYP17, CYP19, and 3betaHSD, all of which are important components of steroidogenic pathways. Sulfathiazole was the most potent compound affecting steroidogenesis in H295R cells, followed by chlortetracycline and oxytetracycline. Sulfathiazole significantly increased aromatase activity at 0.2 mg/l. In medaka fish, concentrations of E2 in plasma increased significantly during 14-d exposure to 50 or 500 mg/l sulfathiazole, or 40 mg/l chlortetracycline. Based on the results of this study, certain pharmaceuticals could affect steroidogenic pathway and alter sex hormone balance. Concentrations of the pharmaceuticals studied that have been reported to occur in rivers of Korea are much less than the thresholds for effects on the endpoints studied here. Thus, it is unlikely that these pharmaceuticals are causing adverse effects on fish in those rivers.

Evaul K, Li R, Papari-Zareei M, et al.
3beta-hydroxysteroid dehydrogenase is a possible pharmacological target in the treatment of castration-resistant prostate cancer.
Endocrinology. 2010; 151(8):3514-20 [PubMed] Related Publications
Prostate cancer usually responds to androgen deprivation therapy, although the response in metastatic disease is almost always transient and tumors eventually progress as castration-resistant prostate cancer (CRPC). CRPC continues to be driven by testosterone or dihydrotestosterone from intratumoral metabolism of 19-carbon adrenal steroids from circulation, and/or de novo intratumoral steroidogenesis. Both mechanisms require 3beta-hydroxysteroid dehydrogenase (3betaHSD) metabolism of Delta(5)-steroids, including dehydroepiandrosterone (DHEA) and Delta(5)-androstenediol (A5diol), to testosterone. In contrast, reports that DHEA and A5diol directly activate the androgen receptor (AR) suggest that 3betaHSD metabolism is not required and that 3betaHSD inhibitors would be ineffective in the treatment of CRPC. We hypothesized that activation of AR in prostate cancer by DHEA and A5diol requires their conversion via 3betaHSD to androstenedione and testosterone, respectively. Here, we show that DHEA and A5diol induce AR chromatin occupancy and AR-regulated genes. Furthermore, we show that Delta(5)-androgens undergo 3beta-dehydrogenation in prostate cancer and that induction of AR nuclear translocation, AR chromatin occupancy, transcription of PSA, TMPRSS2, and FKBP5, as well as cell proliferation by DHEA and A5diol, are all blocked by inhibitors of 3betaHSD. These findings demonstrate that DHEA and A5diol must be metabolized by 3betaHSD to activate AR in these models of CRPC. Furthermore, this work suggests that 3betaHSD may be exploited as a pharmacologic target in the treatment of CRPC.

Hofland J, van Weerden WM, Dits NF, et al.
Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer.
Cancer Res. 2010; 70(3):1256-64 [PubMed] Related Publications
Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC.

Setlur SR, Chen CX, Hossain RR, et al.
Genetic variation of genes involved in dihydrotestosterone metabolism and the risk of prostate cancer.
Cancer Epidemiol Biomarkers Prev. 2010; 19(1):229-39 [PubMed] Related Publications
PURPOSE: Dihydrotestosterone (DHT) is an important factor in prostate cancer (PCA) genesis and disease progression. Given PCA's strong genetic component, we evaluated the possibility that variation in genes involved in DHT metabolism influence PCA risk.
EXPERIMENTAL DESIGN: We investigated copy number variants (CNV) and single nucleotide polymorphisms (SNP). We explored associations between CNV of uridine diphospho-glucuronosyltransferase (UGT) genes from the 2B subclass, given their prostate specificity and/or involvement in steroid metabolism and PCA risk. We also investigated associations between SNPs in genes (HSD3B1, SRD5A1/2, and AKR1C2) involved in the conversion of testosterone to DHT, and in DHT metabolism and PCA risk. The population consisted of 426 men (205 controls and 221 cases) who underwent prostate-specific antigen screening as part of a PCA early detection program in Tyrol, Austria.
RESULTS: No association between CNV in UGT2B17 and UGT2B28 and PCA risk was identified. Men carrying the AA genotype at SNP rs6428830 (HSD3B1) had an odds ratio (OR) of 2.0 [95% confidence intervals (95% CI), 1.1-4.1] compared with men with GG, and men with AG or GG versus AA in rs1691053 (SRD5A1) had an OR of 1.8 (95% CI, 1.04-3.13). Individuals carrying both risk alleles had an OR of 3.1 (95% CI, 1.4-6.7) when compared with men carrying neither (P = 0.005). Controls with the AA genotype on rs7594951 (SRD5A2) tended toward higher serum DHT levels (P = 0.03).
CONCLUSIONS: This is the first study to implicate the 5alpha-reductase isoform 1 (SRD5A1) and PCA risk, supporting the rationale of blocking enzymatic activity of both isoforms of 5alpha-reductase for PCA chemoprevention.

Ramayya MS, Sheng M, Moroz K, et al.
Human steroidogenic factor-1 (hSF-1) regulates progesterone biosynthesis and growth of ovarian surface epithelial cancer cells.
J Steroid Biochem Mol Biol. 2010; 119(1-2):14-25 [PubMed] Related Publications
The majority of cancers derived from ovarian surface epithelial (OSE) cells are lethal. Estrogens promote proliferation of OSE cells, whereas progesterone inhibits proliferation and promotes apoptosis of OSE cells. Human steroidogenic factor-1 (hSF-1) induction of the steroidogenic acute regulatory protein (StAR) gene, and the steroidogenic enzymes CYP11A1 and HSD3B2 is central to progesterone biosynthesis. Whereas hSF-1 and StAR are expressed in human ovarian surface epithelial (HOSE) cells, hSF-1 and StAR protein were not expressed in a panel of malignant ovarian cancer cell lines (SKOV-3, BG-1, and Caov-3), and in human OSE cells immortalized by SV40 large T antigen (IOSE-121). Transient expression of hSF-1 in SKOV-3 cells activated the expression of StAR, p450scc and 3betaHSD-II mRNAs, and induced progesterone biosynthesis. Additionally, hSF-1 suppressed proliferation and promoted apoptosis of SKOV-3 cells and suppressed SKOV-3 cell growth induced by ERalpha and estradiol. These findings suggest that hSF-1 is central to progesterone biosynthesis in OSE cells. Human SF-1 may decrease OSE cancer cell numbers directly by apoptosis, and indirectly by opposing estradiol-induced proliferation. These findings are consistent with the hypothesis, that down-regulation of hSF-1 contributes to progression of ovarian epithelial cancers.

Beuten J, Gelfond JA, Franke JL, et al.
Single and multigenic analysis of the association between variants in 12 steroid hormone metabolism genes and risk of prostate cancer.
Cancer Epidemiol Biomarkers Prev. 2009; 18(6):1869-80 [PubMed] Related Publications
To estimate the prostate cancer risk conferred by individual single nucleotide polymorphisms (SNPs), SNP-SNP interactions, and/or cumulative SNP effects, we evaluated the association between prostate cancer risk and the genetic variants of 12 key genes within the steroid hormone pathway (CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1). A total of 116 tagged SNPs covering the group of genes were analyzed in 2,452 samples (886 cases and 1,566 controls) in three ethnic/racial groups. Several SNPs within CYP19 were significantly associated with prostate cancer in all three ethnicities (P = 0.001-0.009). Genetic variants within HSD3B2 and CYP24A1 conferred increased risk of prostate cancer in non-Hispanic or Hispanic Caucasians. A significant gene-dosage effect for increasing numbers of potential high-risk genotypes was found in non-Hispanic and Hispanic Caucasians. Higher-order interactions showed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic Caucasians (P = 0.001). In African Americans, a 10-locus model, with SNPs located within SRD5A2, HSD17B3, CYP17, CYP27B1, CYP19, and CYP24A1, showed a significant interaction (P = 0.014). In non-Hispanic Caucasians, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P < 0.001). These data are consistent with a polygenic model of prostate cancer, indicating that multiple interacting genes of the steroid hormone pathway confer increased risk of prostate cancer.

Montgomery RB, Mostaghel EA, Vessella R, et al.
Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth.
Cancer Res. 2008; 68(11):4447-54 [PubMed] Free Access to Full Article Related Publications
Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.

Ross RW, Oh WK, Xie W, et al.
Inherited variation in the androgen pathway is associated with the efficacy of androgen-deprivation therapy in men with prostate cancer.
J Clin Oncol. 2008; 26(6):842-7 [PubMed] Related Publications
PURPOSE: Androgen-deprivation therapy (ADT) is the most common and effective systemic therapy for advanced prostate cancer. We hypothesized that germline genetic variation in the androgen axis would improve the efficacy of ADT.
PATIENTS AND METHODS: A cohort of 529 men with advanced prostate cancer treated with ADT was genotyped for 129 DNA polymorphisms distributed across 20 genes involved in androgen metabolism.
RESULTS: Three polymorphisms in separate genes (CYP19A1, HSD3B1, and HSD17B4) were significantly (P < .01) associated with time to progression (TTP) during ADT, remaining so in multivariate analyses and after correcting for the number of hypotheses tested. Individuals carrying more than one of the polymorphisms associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one (P < .0001).
CONCLUSION: This report is the first to examine the influence of inherited variation in the androgen metabolic pathway on the efficacy of ADT, establishing the importance of pharmacogenomics on individual's response to this therapy. At least two potential clinical benefits may be realized from this study. The first is prognostic -genotyping patients at these loci may yield important information that could improve efficacy prediction. The second is therapeutic -these results shed light on the pathways that govern response to ADT. Drugs could be developed (or may already exist) to inhibit or augment these targets to improve ADT efficacy.

Mao TL, Kurman RJ, Jeng YM, et al.
HSD3B1 as a novel trophoblast-associated marker that assists in the differential diagnosis of trophoblastic tumors and tumorlike lesions.
Am J Surg Pathol. 2008; 32(2):236-42 [PubMed] Related Publications
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.

Carruba G
Estrogen and prostate cancer: an eclipsed truth in an androgen-dominated scenario.
J Cell Biochem. 2007; 102(4):899-911 [PubMed] Related Publications
Prostate cancer is the commonest non-skin cancer in men. Incidence and mortality rates of this tumor vary strikingly throughout the world. Although several factors have been implicated to explain this remarkable variation, lifestyle and dietary factors may play a dominant role, with sex hormones behaving as intermediaries between exogenous factors and molecular targets in development and progression of prostate cancer. Human prostate cancer is generally considered a paradigm of androgen-dependent tumor; however, estrogen role in both normal and malignant prostate appears to be equally important. The association between plasma androgens and prostate cancer remains contradictory and mostly not compatible with the androgen hypothesis. Similar evidence apply to estrogens, although the ratio of androgen to estrogen in plasma declines with age. Apart from methodological problems, a major issue is to what extent circulating hormones can be considered representative of their intraprostatic levels. Both nontumoral and malignant human prostate tissues and cells are endowed with key enzymes of steroid metabolism, including 17betahydroxysteroid dehydrogenase (17betaHSD), 5beta-reductase, 3alpha/3betaHSD, and aromatase. A divergent expression and/or activity of these enzymes may eventually lead to a differential prostate accumulation of steroid derivatives having distinct biological activities, as it occurs for hydroxylated estrogens in the human breast. Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression. Interestingly, many genes encoding for steroid enzymes are polymorphic, although only a few studies have supported their relation with risk of prostate cancer. In animal model systems estrogens, combined with androgens, appear to be required for the malignant transformation of prostate epithelial cells. Although the mechanisms underlying the hormonal induction of prostate cancer in experimental animals remain uncertain, there is however evidence to support the assumption that long term administration of androgens and estrogens results in an estrogenic milieu in rat prostates and in the ensuing development of dysplasia and cancer. Both androgen and estrogen have been reported to stimulate proliferation of cultured prostate cancer cells, primarily through receptor-mediated effects. As for estrogens, the two major receptor types, ERalpha and ERbeta, are expressed in both normal and diseased human prostate, though with a different cellular localization. Since these two receptors are different in terms of ligand binding, heterodimerization, transactivation, and estrogen response element activity, it is likely that an imbalance of their expression may be critical to determine the ultimate estrogen effects on prostate cancer cells. In prostate cancer, ERbeta activation appears to limit cell proliferation directly or through ERalpha inhibition, and loss of ERbeta has been consistently associated with tumor progression. Several splicing variants of both ERalpha and ERbeta exist. Little is known about their expression and function in the human prostate, although reciprocal regulation and interaction with gene promoter both warrant further investigation. In summary, although multiple consistent evidence suggests that estrogens are critical players in human prostate cancer, their role has been only recently reconsidered, being eclipsed for years by an androgen-dominated interest.

Stone J, Gurrin LC, Byrnes GB, et al.
Mammographic density and candidate gene variants: a twins and sisters study.
Cancer Epidemiol Biomarkers Prev. 2007; 16(7):1479-84 [PubMed] Related Publications
BACKGROUND: Mammographic density, the light/white radiographic appearance on a mammogram that represents connective and epithelial tissue, is a strong risk factor for breast cancer which seems to be highly heritable. Little is known about its genetic determinants.
METHODS: We studied 457 women from 207 sisterhoods (104 monozygotic twins, 182 dizygotic twins, and 171 singletons). Percentage mammographic density (PMD) as well as dense area and nondense area were calculated using a computer-assisted method. We measured six single nucleotide polymorphisms from six candidate genes (COMT, HSD3B1, IGFBP3, HER2, XPD, and XRCC3). Associations between genotypes and mammographic measures were tested (a) cross-sectionally using a multivariate normal model fitted using FISHER that allowed separate correlations for monozygotic, dizygotic, and nontwin pairs and (b) within sister pairs using paired t tests.
RESULTS: Cross-sectionally, each additional copy of the HSD3B1 Asn(367)Thr variant allele was associated with lower PMD (-3.47% per allele; SE = 1.65; P = 0.035). Within-pair regression estimates confirmed this association. There was no evidence for an association between the mammographic density measures and any of the other variants studied.
CONCLUSION: We have replicated an association between a variant in the HSD3B1 gene and PMD, which suggests that HSD3B1 may be genetic determinant of mammographic density.

Cunningham JM, Hebbring SJ, McDonnell SK, et al.
Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer.
Cancer Epidemiol Biomarkers Prev. 2007; 16(5):969-78 [PubMed] Related Publications
Previous studies suggest that enzymes involved in the androgen metabolic pathway are susceptibility factors for prostate cancer. Estrogen metabolites functioning as genotoxins have also been proposed as risk factors. In this study, we systematically tested the hypothesis that common genetic variations for those enzymes involved in the androgen and estrogen metabolic pathways increase risk for sporadic and familial prostate cancer. From these two pathways, 46 polymorphisms (34 single nucleotide polymorphisms, 10 short tandem repeat polymorphisms, and 2 null alleles) in 25 genes were tested for possible associations. Those genes tested included PRL, LHB, CYP11A1, HSD3B1, HSD3B2, HSD17B2, CYP17, SRD5A2, AKR1C3, UGT2B15, AR, SHBG, and KLK3 from the androgen pathway and CYP19, HSD17B1, CYP1A1, CYP1A2, CYP1B1, COMT, GSTP1, GSTT1, GSTM1, NQO1, ESR1, and ESR2 from the estrogen pathway. A case-control study design was used with two sets of cases: familial cases with a strong prostate cancer family history (n = 438 from 178 families) and sporadic cases with a negative prostate cancer family history (n = 499). The controls (n = 493) were derived from a population-based collection. Our results provide suggestive findings for an association with either familial or sporadic prostate cancer with polymorphisms in four genes: AKR1C3, HSD17B1, NQO1, and GSTT1. Additional suggestive findings for an association with clinical variables (disease stage, grade, and/or node status) were observed for single nucleotide polymorphisms in eight genes: HSD3B2, SRD5A2, SHBG, ESR1, CYP1A1, CYP1B1, GSTT1, and NQO1. However, none of the findings were statistically significant after appropriate corrections for multiple comparisons. Given that the point estimates for the odds ratio for each of these polymorphisms are <2.0, much larger sample sizes will be required for confirmation.

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