Gene Summary

Gene:HSD17B1; hydroxysteroid 17-beta dehydrogenase 1
Aliases: E2DH, HSD17, EDHB17, EDH17B2, SDR28C1, 17-beta-HSD, 20-alpha-HSD
Summary:This gene encodes a member of the 17beta-hydroxysteroid dehydrogenase family of short-chain dehydrogenases/reductases. It has a dual function in estrogen activation and androgen inactivation and plays a major role in establishing the estrogen E2 concentration gradient between serum and peripheral tissues. The encoded protein catalyzes the last step in estrogen activation, using NADPH to convert estrogens E1 and E2 and androgens like 4-androstenedione, to testosterone. It has an N-terminal short-chain dehydrogenase domain with a cofactor binding site, and a narrow, hydrophobic C-terminal domain with a steroid substrate binding site. This gene is expressed primarily in the placenta and ovarian granulosa cells, and to a lesser extent, in the endometrium, adipose tissue, and prostate. Polymorphisms in this gene have been linked to breast and prostate cancer. A pseudogene of this gene has been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:estradiol 17-beta-dehydrogenase 1
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (10)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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.

  • United Kingdom
  • Gonadal Steroid Hormones
  • Sulfotransferases
  • Cohort Studies
  • Genetic Predisposition
  • Receptor, erbB-2
  • Cytochrome P-450 Enzyme System
  • Estradiol Dehydrogenases
  • Cancer Gene Expression Regulation
  • Cytochrome P-450 CYP1A1
  • Estrogen Receptor alpha
  • Case-Control Studies
  • Hydroxysteroid Dehydrogenases
  • Chromosome 17
  • Endometrial Cancer
  • Prostate Cancer
  • Estradiol
  • 17-Hydroxysteroid Dehydrogenases
  • Polymorphism
  • Stomach Cancer
  • Androgens
  • Catechol O-Methyltransferase
  • Genotype
  • CYP17
  • Genetic Association Studies
  • Breast Cancer
  • Odds Ratio
  • Haplotypes
  • Single Nucleotide Polymorphism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Aromatase
  • Base Sequence
  • Colorectal Cancer
  • Thailand
  • Aryl Hydrocarbon Hydroxylases
  • Genetic Variation
  • Messenger RNA
  • Estrogens
  • Postmenopause
  • Neoplasm Proteins
  • Polymerase Chain Reaction
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: HSD17B1 (cancer-related)

Li F, Zhu Z, Xue M, et al.
siRNA-based breast cancer therapy by suppressing 17β-hydroxysteroid dehydrogenase type 1 in an optimized xenograft cell and molecular biology model in vivo.
Drug Des Devel Ther. 2019; 13:757-766 [PubMed] Free Access to Full Article Related Publications
Purpose: Hormone-dependent breast cancer is the most common form of breast cancer, and inhibiting 17β-HSD1 can play an attractive role in decreasing estrogen and cancer cell proliferation. However, the majority of existing inhibitors have been developed from estrogens and inevitably possess residual estrogenicity. siRNA knockdown provides a highly specific way to block a targeted enzyme, being especially useful to avoid estrogenicity. Application of 17β-HSD1-siRNA in vivo is limited by the establishment of an animal model, as well as the potential nuclease activity in vivo. We tried to reveal the in vivo potential of 17β-HSD1-siRNA-based breast cancer therapy.
Materials and methods: To establish a competent animal model, daily subcutaneous injection of an estrone micellar aqueous solution was adopted to provide the substrate for estradiol biosynthesis. The effects of three different doses of estrone (0.1, 0.5, and 2.5 µg/kg/day) on tumor growth in T47D-17β-HSD1-inoculated group were investigated and compared with the animals inoculated with wild type T47D cells. To solve in vivo delivery problem of siRNA, "17β-HSD1-siRNA/LPD", a PEGylated and modified liposome-polycation-DNA nanoparticle containing 17β-HSD1-siRNA was prepared by the thin film hydration method and postinsertion technology. Finally, "17β-HSD1-siRNA/LPD" was tested in the optimized model. Tumor growth and 17β-HSD1 expression were assessed.
Results: Comparison with the untreated group revealed significant suppression of tumor growth in "17β-HSD1-siRNA/LPD"-treated group when HSD17B1 gene expression was knocked down.
Conclusion: These findings showed promising in vivo assessments of 17β-HSD1-siRNA candidates. This is the first report of an in vivo application of siRNA for steroid-converting enzymes in a nude mouse model.

Sang X, Han H, Poirier D, Lin SX
Steroid sulfatase inhibition success and limitation in breast cancer clinical assays: An underlying mechanism.
J Steroid Biochem Mol Biol. 2018; 183:80-93 [PubMed] Related Publications
Steroid sulfatase is detectable in most hormone-dependent breast cancers. STX64, an STS inhibitor, induced tumor reduction in animal assay. Despite success in phase І clinical trial, the results of phase II trial were not that significant. Breast Cancer epithelial cells (MCF-7 and T47D) were treated with two STS inhibitors (STX64 and EM1913). Cell proliferation, cell cycle, and the concentrations of estradiol and 5α-dihydrotestosterone were measured to determine the endocrinological mechanism of sulfatase inhibition. Comparisons were made with inhibitions of reductive 17β-hydroxysteroid dehydrogenases (17β-HSDs). Proliferation studies showed that DNA synthesis in cancer cells was modestly decreased (approximately 20%), accompanied by an up to 6.5% in cells in the G0/G1 phase and cyclin D1 expression reduction. The concentrations of estradiol and 5α-dihydrotestosterone were decreased by 26% and 3% respectively. However, supplementation of 5α-dihydrotestosterone produced a significant increase (approximately 35.6%) in the anti-proliferative effect of sulfatase inhibition. This study has clarified sex-hormone control by sulfatase in BC, suggesting that the different roles of estradiol and 5α-dihydrotestosterone can lead to a reduction in the effect of sulfatase inhibition when compared with 17β-HSD7 inhibition. This suggests that combined treatment of sulfatase inhibitors with 17β-HSD inhibitors such as the type7 inhibitor could hold promise for hormone-dependent breast cancer.

Savolainen-Peltonen H, Vihma V, Wang F, et al.
Estrogen biosynthesis in breast adipose tissue during menstrual cycle in women with and without breast cancer.
Gynecol Endocrinol. 2018; 34(12):1039-1043 [PubMed] Related Publications
Circulating estrogens fluctuate during the menstrual cycle but it is not known whether this fluctuation is related to local hormone levels in adipose tissue. We analyzed estrogen concentrations and gene expression of estrogen-regulating enzymes in breast subcutaneous adipose tissue in premenopausal women with (n = 11) and without (n = 17) estrogen receptor-positive breast cancer. Estrone (E

Belani M, Deo A, Shah P, et al.
Differential insulin and steroidogenic signaling in insulin resistant and non-insulin resistant human luteinized granulosa cells-A study in PCOS patients.
J Steroid Biochem Mol Biol. 2018; 178:283-292 [PubMed] Related Publications
Insulin resistance (IR) is one of the significant aberrations in polycystic ovarian syndrome (PCOS), however is only observed in 70%-80% of obese PCOS and 20%-25% of lean PCOS. Hyperinsulinemia accompanies PCOS-IR along with hyperandrogenemia against normal insulin and androgen levels in PCOS-non insulin resistance (NIR). This could possibly be due to defects in the downstream signaling pathways. The study thus aims to unravel insulin and steroidogenic signaling pathways in luteinized granulosa cells isolated from PCOS-IR and NIR vs matched controls. Luteinized granulosa cells from 30 controls and 39 PCOS were classified for IR based on a novel method of down regulation of protein expression of insulin receptor-β (INSR- β) as shown in our previous paper. We evaluated expression of molecules involved in insulin, steroidogenic signaling and lipid metabolism in luteinized granulosa cells followed by analysis of estradiol, progesterone and testosterone in follicular fluid. Protein expression of INSR- β, pIRS (ser 307), PI(3)K, PKC-ζ, pAkt, ERK1/2, pP38MAPK and gene expression of IGF showed differential expression in the two groups. Increased protein expression of PPAR-γ was accompanied by up regulation in SREBP1c, FAS, CPT-1 and ACC-1 genes in PCOS-IR group. Expression of StAR, CYP19A1, 17 β- HSD and 3 β- HSD demonstrated significant decrease along with increase in CYP11A1, FSH-R and LH-R in both the groups. Follicular fluid testosterone increased and progesterone decreased in PCOS-IR group. This study shows how candidate molecules that were differentially expressed, aid in designing targeted therapy against the two phenotypes of PCOS.

Tang L, Platek ME, Yao S, et al.
Associations between polymorphisms in genes related to estrogen metabolism and function and prostate cancer risk: results from the Prostate Cancer Prevention Trial.
Carcinogenesis. 2018; 39(2):125-133 [PubMed] Free Access to Full Article Related Publications
Substantial preclinical data suggest estrogen's carcinogenic role in prostate cancer development; however, epidemiological evidence based on circulating estrogen levels is largely null. Compared with circulating estrogen, the intraprostatic estrogen milieu may play a more important role in prostate carcinogenesis. Using a nested case-control design in the Prostate Cancer Prevention Trial (PCPT), we examined associations of genetic variants of genes that are involved in estrogen synthesis, metabolism and function with prostate cancer risk. A total of 25 potentially functional single nucleotide polymorphisms (SNPs) in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined in whites only. Controls (n = 1380) were frequency matched to cases on age, PCPT treatment arm, and family history (n = 1506). Logistic regression models adjusted for age and family history were used to estimate odds ratios (OR) and 95% confidence intervals (CI) separately in the placebo and finasteride arms. SNPs associated with prostate cancer risk differed by treatment arm. The associations appeared to be modified by circulating estrogen and androgen levels. CYP19A1 was the only gene harboring SNPs that were significantly associated with risk in both the placebo and finasteride arms. Haplotype analysis with all three CYP19A1 SNPs genotyped (rs700518, rs2445765, rs700519) showed that risk-allele haplotypes are associated with the increased prostate cancer risk in both arms when comparing with the non-risk allele haplotype. In conclusion, associations between SNPs in estrogen-related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment.

Hilborn E, Stål O, Jansson A
Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer.
Oncotarget. 2017; 8(18):30552-30562 [PubMed] Free Access to Full Article Related Publications
Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of the breast tissue. The activity and concentration of sex steroids is determined by the availability from the circulation, and on local conversion. This conversion is primarily mediated by aromatase, steroid sulfatase, and 17β-hydroxysteroid dehydrogenases. In postmenopausal women, this is the primary source of estrogens in the breast. Up to 70-80% of all breast cancers express the estrogen receptor-α, responsible for promoting the growth of the tissue. Further, 60-80% express the androgen receptor, which has been shown to have tissue protective effects in estrogen receptor positive breast cancer, and a more ambiguous response in estrogen receptor negative breast cancers. In this review, we summarize the function and clinical relevance in cancer for 17β-hydroxysteroid dehydrogenases 1, which facilitates the reduction of estrone to estradiol, dehydroepiandrosterone to androstendiol and dihydrotestosterone to 3α- and 3β-diol as well as 17β-hydroxysteroid dehydrogenases 2 which mediates the oxidation of estradiol to estrone, testosterone to androstenedione and androstendiol to dehydroepiandrosterone. The expression of 17β-hydroxysteroid dehydrogenases 1 and 2 alone and in combination has been shown to predict patient outcome, and inhibition of 17β-hydroxysteroid dehydrogenases 1 has been proposed to be a prime candidate for inhibition in patients who develop aromatase inhibitor resistance or in combination with aromatase inhibitors as a first line treatment. Here we review the status of inhibitors against 17β-hydroxysteroid dehydrogenases 1. In addition, we review the involvement of 17β-hydroxysteroid dehydrogenases 4, 5, 7, and 14 in breast cancer.

Cornel KM, Krakstad C, Delvoux B, et al.
High mRNA levels of 17β-hydroxysteroid dehydrogenase type 1 correlate with poor prognosis in endometrial cancer.
Mol Cell Endocrinol. 2017; 442:51-57 [PubMed] Related Publications
Most endometrial cancers (ECs) are diagnosed at an early stage and have a good prognosis. However, 20-30% develop recurrence and have poor survival. Recurrence-risk prediction at diagnosis is hampered by the scarcity of prognostic markers. Most ECs are estrogen related, and recent studies show that estrogen exposure in EC is controlled intracrinally. We aim at assessing any association between patient prognosis and the pathways controlling the intracrine estrogen generation in EC: (a) the balance between 17β-hydroxysteroid-dehydrogenase-type 1 (HSD17B1), that generates active estrogens, and HSD17B2, converting active into poorly active compounds; (b) the balance between steroid sulphatase (STS, that activates estrogens) and estrogen-sulphotransferase (SULT1E1, that deactivates estrogens); (c) the levels of aromatase (ARO), that converts androgen into estrogens. mRNA levels of HSD17B1, HSD17B2, STS, SULT1E1 and ARO were determined among 175 ECs using cDNA microarray. Proteins were explored by immunohistochemistry. Patients with high mRNA of HSD17B1 had a poorer prognosis compared with those with low levels. Combining the expression of HSD17B1 and HSD17B2, patients with high tumour expression of HSD17B1 and low levels of HSD17B2 had the poorest prognosis. Contrarily, women that had high tumour levels of HSD17B2 and low of HSD17B1 had the best outcome. No differences were seen between mRNA level of other the genes analysed and prognosis. At the protein level, HSD17B2, STS and SULT1E1 were highly expressed, whereas HSD17B1 was low and ARO was almost absent. In conclusion, HSD17B1 is a promising marker to predict EC prognosis. Immunohistochemical detection of this protein in ECs has low sensitivity and should be improved for future clinical applications.

Chang WC, Huang SF, Lee YM, et al.
Cholesterol import and steroidogenesis are biosignatures for gastric cancer patient survival.
Oncotarget. 2017; 8(1):692-704 [PubMed] Free Access to Full Article Related Publications
Androgens, estrogens, progesterone and related signals are reported to be involved in the pathology of gastric cancer. However, varied conclusions exist based on serum hormone levels, receptor expressions, and in vitro or in vivo studies. This report used a web-based gene survival analyzer to evaluate biochemical processes, including cholesterol importing via lipoprotein/receptors (L/R route), steroidogenic enzymes, and steroid receptors, in gastric cancer patients prognosis. The sex hormone receptors (androgen receptor, progesterone receptor, and estrogen receptor ESR1 or ESR2), L/R route (low/high-density lipoprotein receptors, LDLR/LRP6/SR-B1 and lipoprotein lipase, LPL) and steroidogenic enzymes (CYP11A1, HSD3B1, CYP17, HSD17B1, HSD3B1, CYP19A1 and SRD5A1) were associated with 5-year survival of gastric cancer patients. The AR, PR, ESR1 and ESR2 are progression promoters, as are the L/R route LDLR, LRP6, SR-B1 and LPL. It was found that CYP11A1, HSD3B1, CYP17, HSD17B1 and CYP19A1 promote progression, but dihydrotestosterone (DHT) converting enzyme SRD5A1 suppresses progression. Analyzing steroidogenic lipidome with a hazard ratio score algorithm found that CYP19A1 is the progression confounder in surgery, HER2 positive or negative patients. Finally, in the other patient cohort from TCGA, CYP19A1 was expressed higher in the tumor compared to that in normal counterparts, and also promoted progression. Lastly, exemestrane (type II aromatase inhibitor) dramatically suppress GCa cell growth in pharmacological tolerable doses in vitro. This work depicts a route-specific outside-in delivery of cholesterol to promote disease progression, implicating a host-to-tumor macroenvironmental regulation. The result indicating lipoprotein-mediated cholesterol entry and steroidogenesis are GCa progression biosignatures. And the exemestrane clinical trial in GCa patients of unmet medical needs is suggested.

Lutkowska A, Roszak A, Jagodziński PP
17β-hydroxysteroid dehydrogenase type Gene 1937 A > G Polymorphism as a Risk Factor for Cervical Cancer Progression in the Polish Population.
Pathol Oncol Res. 2017; 23(2):317-322 [PubMed] Related Publications
The role of 17β-estradiol (E2) in the development of cervical tumor (CT) has been demonstrated. 17β Hydroxysteroid dehydrogenase type 1 (HSD17B1) converts estrone (E1) into E2. We aimed to study the distribution of the HSD17B1937 A > G (rs605059) single nucleotide polymorphism (SNP) in women (n = 383) with CT and controls (n = 401) from the Polish population. The p-trend value evaluated for HSD17B1 rs605059 was 0.0233 for all patients. The A/A vs G/G genotype significantly contributed to all patients with CT, and the Odds Ratio (OR) was 1.570 (95 % CI = 1.053-2.343; p = 0.0266). Stratification of the patients based on tumor stage and histological grade indicated the contribution of HSD17B1937 A > G to stages III and IV. The p-value was 0.0010. The OR for the A/A vs G/G genotype was 2.992 (95 % CI = 1.627-5.502, p = 0.0003), the OR for the A/G vs G/G genotype was 2.545 (95 % CI = 1.410-4.593, p = 0.0015) and the OR for the A/A and A/G vs G/G genotype was 2.724 (95 % CI = 1.546-4.799, p = 0.0004). Moreover, we observed a contribution of the rs605059 SNP to histological grade G3 status. The p-value was 0.0042. The OR for the A/A vs G/G genotype was 5.632 (95 % CI = 1.644-19.290, p = 0.0026), the OR for the A/G vs G/G genotype was 4.213 (95 % CI = 1.244-14.265, p = 0.0113) and the OR for the A/A and A/G vs G/G genotype was 4.780 (95 % CI = 1.456-15.687, p = 0.0033). Our study indicated that the HSD17B1937 A > G transition is a risk factor for CT, especially for stages III and IV and histological grade G3.

Aka JA, Calvo EL, Lin SX
Estradiol-independent modulation of breast cancer transcript profile by 17beta-hydroxysteroid dehydrogenase type 1.
Mol Cell Endocrinol. 2017; 439:175-186 [PubMed] Related Publications
17beta-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a steroidal enzyme which, in breast cancer cells, mainly synthesizes 17-beta-estradiol (E2), an estrogenic hormone that stimulates breast cancer cell growth. We previously showed that the enzyme increased breast cancer cell proliferation via a dual effect on E2 and 5α-dihydrotestosterone (DHT) levels and impacted gene expression and protein profile of breast cancer cells cultured in E2-contained medium. Here, we used RNA interference technique combined with microarray analyses to investigate the effect of 17β-HSD1 expression on breast cancer cell transcript profile in steroid-deprived condition. Our data revealed that knockdown of 17β-HSD1 gene, HSD17B1, modulates the transcript profile of the hormone-dependent breast cancer cell line T47D, with 105 genes regulated 1.5 fold or higher (p < 0.05) in estradiol-independent manner. Using Ingenuity Pathway Analysis (IPA), we additionally assessed functional enrichment analyses, including biological functions and canonical pathways, and found that, in concordance with the role of 17β-HSD1 in cancer cell growth, most regulated genes are cancer-related genes. Genes that primarily involved in the cell cycle progression, such as the cyclin A2 gene, CCNA2, are generally down-regulated whereas genes involved in apoptosis and cell death, including the pro-apoptotic gene XAF1, IFIH1 and FGF12, are on the contrary up-regulated by 17β-HSD1 knockdown, and 21% of the modulated genes belong to this latter functional category. This indicates that 17β-HSD1 may be involved in oncogenesis by favoring anti-apoptosis pathway in breast cancer cells and correborates with its previously shown role in increasing breast cancer cell proliferation. The gene regulation occurring in steroid-deprived conditions showed that 17β-HSD1 can modulate endogenous gene expression in steroid-independent manners. Besides, we tested the ability of estrogen to induce or repress endogenous genes of T47D by microarray analysis. Expression of a total of 130 genes were found to increase or decrease 1.5-fold or higher (p < 0.05) in response to E2 treatment (1 nM for 48 h), revealing a list of potential new estrogen-responsive genes and providing useful information for further studies of estrogen-dependent breast cancer mechanisms. In conclusion, in breast cancer cells, in addition to its implication in the E2-dependent gene transcription, the present study demonstrates that 17β-HSD1 also modulates gene expression via mechanisms independent of steroid actions. Those mechanisms that may include the ligand-independent gene transcription of estrogen receptor alpha (ERα), whose expression is positively correlated with that of the enzyme, and that may implicate 17β-HSD1 in anti-apoptosis pathways, have been discussed.

He W, Gauri M, Li T, et al.
Current knowledge of the multifunctional 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1).
Gene. 2016; 588(1):54-61 [PubMed] Free Access to Full Article Related Publications
At the late 1940s, 17β-HSD1 was discovered as the first member of the 17β-HSD family with its gene cloned. The three-dimensional structure of human 17β-HSD1 is the first example of any human steroid converting enzyme. The human enzyme's structure and biological function have thus been studied extensively in the last two decades. In humans, the enzyme is expressed in placenta, ovary, endometrium and breast. The high activity of estrogen activation provides the basis of 17β-HSD1's implication in estrogen-dependent diseases, such as breast cancer, endometriosis and non-small cell lung carcinomas. Its dual function in estrogen activation and androgen inactivation has been revealed in molecular and breast cancer cell levels, significantly stimulating the proliferation of such cells. The enzyme's overexpression in breast cancer was demonstrated by clinical samples. Inhibition of human 17β-HSD1 led to xenograft tumor shrinkage. Unfortunately, through decades of studies, there is still no drug using the enzyme's inhibitors available. This is due to the difficulty to get rid of the estrogenic activity of its inhibitors, which are mostly estrogen analogues. New non-steroid inhibitors for the enzyme provide new hope for non-estrogenic inhibitors of the enzyme.

Shi L, Yang X, Dong X, Zhang B
Polymorphism of HSD17B1 Ser312Gly with Cancer Risk: Evidence from 66,147 Subjects.
Twin Res Hum Genet. 2016; 19(2):136-45 [PubMed] Related Publications
Hydroxysteroid (17-beta)dehydrogenase 1(HSD17B1) plays a central role in sex steroid hormone metabolism. HSD17B1 polymorphic variants may contribute to cancer susceptibility. Numerous investigations have been conducted to assess the association between HSD17B1 Ser312Gly polymorphism and cancer risk in multiple ethnicities, yet these have produced inconsistent results. We therefore performed this comprehensive meta-analysis to attempt to provide a quality assessment of the association of interest. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of associations. After a systematic literature search of several major public databases, 20 studies involving 29,460 cases and 36,687 controls were included in this meta-analysis. No significant association was found between HSD17B1 Ser312Gly polymorphism and cancer risk. However, Ser312Gly polymorphism showed a significantly decreased risk for Caucasians (there were 44,284 Caucasians for analysis, comprising 19,889 cases and 24,395 controls) in the subgroup analysis by ethnicity (dominant: OR = 0.958, 95% CI = 0.919-0.998; and allele comparing: OR = 0.973, 95% CI = 0.947-0.999). And there was the same trend towards risk in the population-based (PB) controls (homozygous: OR = 0.951, 95% CI = 0.908-0.997 and allele comparing: OR = 0.976, 95% CI = 0.954-0.999), but not among Asians or hospital-based (HB) controls. In addition, no association was observed in the stratified analysis for breast cancer studies by source of control, ethnicity and quality score. These findings suggested that the HSD17B1 Ser312Gly polymorphism might confer genetic cancer susceptibility in an ethnic-dependent manner, especially among Caucasians. Well-designed, large-scale studies are warranted to validate these findings.

Mu X, Du X, Yao K, et al.
Association between HSD17B1 rs605059 polymorphisms and the risk of uterine diseases: a systemic review and meta-analysis.
Int J Clin Exp Pathol. 2015; 8(6):6012-8 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to evaluate the HSD17B1 gene polymorphisms in the risks of endometrial cancer, endometriosis and uterine leiomyoma by meta-analysis. A comprehensive electronic search was conducted in PubMed, Medline (Ovid), Embase, Weipu, Wanfang and CNKI. The pooled ORs were performed using the Revman 5.2 softerware. 8 case-control studies were included: 3 were about endometrial cancer, 4 were about endometriosis and 1 was about uterine leiomyoma. The result showed no significant association between HSD17B1 rs605059 gene polymorphisms and risks of endometrial cancer (AA vs. AG+GG: OR = 1.11, 95% CI = 0.94-1.32; AA+AG vs. GG: OR = 1.79, 95% CI = 0.42-7.52; AG vs. AA+ GG: OR = 0.87, 95% CI = 0.76-1.00; AA vs. GG: OR = 1.43, 95% CI = 0.62-3.30; A vs. G: OR = 1.00, 95% CI = 0.91-1.11) or endometriosis (AA vs. AG+GG: OR = 0.99, 95% CI = 0.75-1.32; AA+AG vs. GG: OR = 1.73, 95% CI = 0.92-3.25; AG vs. AA+ GG: OR = 1.24, 95% CI = 1.00-1.53; AA vs. GG: OR = 1.54, 95% CI = 0.79-2.97; A vs. G: OR = 1.23, 95% CI = 0.90-1.68). No association was found in a subgroup analysis based on Asian ethnicity for endometriosis. This meta-analysis suggested that HSD17B1 rs605059 polymorphisms were not associated with the risks of endometrial cancer and endometriosis. Further studies are needed to validate the conclusion and clarify the relationship between HSD17B1 rs605059 polymorphisms and the risk of uterine leiomyoma.

Tomaszewska A, Roszak A, Pawlik P, et al.
Increased 17ß-hydroxysteroid dehydrogenase type 1 levels in primary cervical cancer.
Biomed Pharmacother. 2015; 72:179-83 [PubMed] Related Publications
Infections with oncogenic human papillomavirus (HPV) strains are recognized as the major risk factor for developing malignant lesions in the uterine cervix. However, several findings have demonstrated cooperation between HPV infection and 17β-estradiol (E2) in cervical carcinogenesis. The 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) is the enzyme involved in the transformation of estrone (E1) into E2. In this study, we identified the HSD17B1 transcript and protein in HeLa, SiHa, Ca Ski and C-33A cervical cancer cells. These cells were able to convert E1 to E2 in a time-dependent manner. Moreover, we identified the HSD17B1 transcript and protein in primary cancerous tissues (n=28) and in histologically unchanged tissues (n=25). We did not observe significant differences (P=0.33) between the HSD17B1 transcript levels in cancerous tissues and histologically unchanged tissues. However, we found an overrepresentation of the HSD17B1 protein in cancerous tissues compared with histologically unchanged tissues (P<0.001). This overrepresentation of the HSD17B1 protein in primary cervical cancerous tissues may be responsible for the local conversion of E1 to E2.

Drzewiecka H, Gałęcki B, Jarmołowska-Jurczyszyn D, et al.
Increased expression of 17-beta-hydroxysteroid dehydrogenase type 1 in non-small cell lung cancer.
Lung Cancer. 2015; 87(2):107-16 [PubMed] Related Publications
OBJECTIVES: Recent studies indicated that estrogens may influence the development of non-small cell lung cancer (NSCLC). The 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) catalyzes the reduction of estrone (E1) to the highly potent E2. Although the significance of aromatase in an intratumoral E2 production in NSCLC is well established, the role of HSD17B1 remains largely unknown. Therefore, we investigated the expression of HSD17B1 in lung cancerous and corresponding histopathologically unchanged tissues from NSCLC patients and the association between HSD17B1 expression and clinicopathological features. Than, we examined the biological significance of HSD17B1 in NSCLC cells in vitro. We tested the impact of 5-Aza-2'-deoxycytidine (5-dAzaC) on HSD17B1 expression and activity.
MATERIALS AND METHODS: We used Real Time quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry to evaluate HSD17B1 expression in tissues obtained from 48 patients with NSCLC. The methylation status of the promoter region of HSD17B1 in A549 and Calu-1 cells was evaluated by bisulfite sequencing. We investigated the effect of 5-dAzaC on HSD17B1 transcript levels (by RT-qPCR) and on HSD17B1 enzyme activity by measuring the conversion of E1 to E2. The xCELLigence System was used for monitoring of cell proliferation.
RESULTS: We found a substantial increase of HSD17B1 mRNA and protein amount in NSCLC tissues compared with histopathologically unchanged tissues in the group of male patients. An overexpression of HSD17B1 was associated with squamous cell carcinoma and with lung cancer stage 3A. We showed that 5-dAzaC induces DNA demethylation of HSD17B1 promoter, leading to increased HSD17B1 mRNA levels and protein activity in NSCLC cells. It resulted in enhanced E2 production in both cell lines and supported the proliferation of Calu-1 cells but not A549 cells.
CONCLUSION: Increased expression of HSD17B1 in NSCLC may contribute to an elevated intratissue level of E2 and consequently may support the development and spread of cancer.

Hevir-Kene N, Rižner TL
The endometrial cancer cell lines Ishikawa and HEC-1A, and the control cell line HIEEC, differ in expression of estrogen biosynthetic and metabolic genes, and in androstenedione and estrone-sulfate metabolism.
Chem Biol Interact. 2015; 234:309-19 [PubMed] Related Publications
Estrogens have important roles in the pathogenesis of endometrial cancer. They can have carcinogenic effects through stimulation of cell proliferation or formation of DNA-damaging species. To characterize model cell lines of endometrial cancer, we determined the expression profiles of the estrogen receptors (ERs) ESR1, ESR2 and GPER, and 23 estrogen biosynthetic and metabolic genes, and investigated estrogen biosynthesis in the control HIEEC cell line and the Ishikawa and HEC-1A EC cell lines. HIEEC and Ishikawa expressed all ERs to different extents, while HEC-1A cells lacked expression of ESR1. Considering the estrogen biosynthetic and metabolic enzymes, these cells showed statistically significant different gene expression profiles for SULT2B1, HSD3B2, CYP19A1, AKR1C3, HSD17B1, HSD17B7, HSD17B12, CYP1B1, CYP3A5, COMT, SULT1A1, GSTP1 and NQO2. In these cells, E2 was formed from E1S and E1, while androstenedione was not converted to estrogens. HIEEC and Ishikawa had similar profiles of androstenedione and E1 metabolism, but hydrolysis of E1S to E1 was weaker in Ishikawa cells. HEC-1A cells were less efficient for activation of E1 into the potent E2, but metabolized androstenedione to other androgenic metabolites better than HIEEC and Ishikawa cells. This study reveals that HIEEC, Ishikawa, and HEC-1A cells can all form estrogens only via the sulfatase pathway. HIEEC, Ishikawa, and HEC-1A cells expressed all the major genes in the production of hydroxyestrogens and estrogen quinones, and in their conjugation. Significantly higher CYP1B1 mRNA levels in Ishikawa cells compared to HEC-1A cells, together with lack of UGT2B7 expression, indicate that Ishikawa cells can accumulate more toxic estrogen-3,4-quinones than HEC-1A cells, as also for HIEEC cells. This study provides further characterization of HIEEC, Ishikawa, and HEC-1A cells, and shows that they differ greatly in expression of the genes investigated and in their capacity for E2 formation, and thus they represent different in vitro models.

Eriksen MB, Glintborg D, Nielsen MF, et al.
Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance.
Biochem Biophys Res Commun. 2014; 451(4):622-6 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls. Glucose transport in myotubes was comparable in patients with PCOS vs. controls and was unchanged by testosterone treatment (p=0.21 PCOS vs. controls). These results suggest that testosterone treatment of myotubes increases the aromatase and androgen receptor gene expression without affecting insulin sensitivity and if testosterone is implicated in muscular insulin resistance in PCOS, this is by and indirect mechanism.

Zhang LS, Yuan F, Guan X, et al.
Association of genetic polymorphisms in HSD17B1, HSD17B2 and SHBG genes with hepatocellular carcinoma risk.
Pathol Oncol Res. 2014; 20(3):661-6 [PubMed] Related Publications
Genetic polymorphisms of enzymes involved in estrogen synthesizing/transporting can influence the risk of hormone-dependent diseases. The incidence rate and relative risk for hepatocellular carcinoma (HCC) are higher in men than in women. This study was conducted to explore the relationship of single nucleotide polymorphisms (SNPs) in 17 β-Hydroxysteroid dehydrogenases (HSD17B1 and HSD17B2) and sex hormone-binding globulin (SHBG) genes with the risk of HCC within Chinese Han population. Polymorphisms of HSD17B1 rs676387, HSD17B2 rs8191246 and SHBG rs6259 were genotyped in 253 HCC patients and 438 healthy control subjects using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Significantly increased HCC risk was found to be associated with T allele of rs676387 and G allele of rs8191246. Increased HCC risks were found in different genetic model (TT genotype in a recessive model, T allele carriers in a dominant model, TT genotype and TG genotype in a codominant model for HSD17B1 rs676387, G allele carriers in a dominant model and AG genotype in a codominant model for HSD17B2 rs8191246, respectively). No association between SHBG rs6259 and HCC risk was observed. The present study provided evidence that HSD17B1 rs676387 and HSD17B2 rs8191246 were association with HCC development. Further studies in diverse ethnic population with larger sample size were recommended to confirm the findings.

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.

Liu L, Bai YX, Zhou JH, et al.
A polymorphism at the 3'-UTR region of the aromatase gene is associated with the efficacy of the aromatase inhibitor, anastrozole, in metastatic breast carcinoma.
Int J Mol Sci. 2013; 14(9):18973-88 [PubMed] Free Access to Full Article Related Publications
Estrogen-related genes and the fat mass and obesity-associated (FTO) gene play a critical role in estrogen metabolism, and those polymorphisms are associated with a poor prognosis in breast cancer. However, little is known about the association between these polymorphisms and the efficacy of anastrozole. The aim was to investigate the impact of the genetic polymorphisms, CYP19A1, 17-β-HSD-1 and FTO, on the response to anastrozole in metastatic breast carcinoma (MBC) and to evaluate the impact of those polymorphisms on various clinicopathologic features. Two-hundred seventy-two women with hormone receptor-positive MBC treated with anastrozole were identified retrospectively. DNA was extracted from peripheral blood and genotyped for five variants in three candidate genes. Time to progression was improved in patients carrying the variant alleles of rs4646 when compared to patients with the wild-type allele (16.40 months versus 13.52 months; p = 0.049). The rs4646 variant alleles were significantly associated with longer overall survival (37.3 months versus 31.6 months; p = 0.007). This relationship was not observed with the rs10046, rs2830, rs9926298 and rs9939609 polymorphisms. The findings of this study indicate that rs4646 polymorphism in the CYP19A1 gene may serve as a prognostic maker of the response to anastrozole in patients with MBC who are treated with anastrozole.

Obazee O, Justenhoven C, Winter S, et al.
Confirmation of the reduction of hormone replacement therapy-related breast cancer risk for carriers of the HSD17B1_937_G variant.
Breast Cancer Res Treat. 2013; 138(2):543-8 [PubMed] Related Publications
17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) plays an important role in the biosynthesis of 17β-estradiol. The current study aimed at confirming the reduced risk of breast cancer in carriers of the non-synonymous HSD17B1_937_A>G (rs605059) polymorphism who used any hormone replacement therapy (HRT) for 10 years or longer. We performed an independent association study using four breast cancer case-control studies from Australia, Germany, and Sweden. In all, 5,777 cases and 8,189 age-matched controls of European descent were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and TaqMan. Risk estimates were calculated by interaction analysis and main effect analysis adjusted for age and study. Main effect analyses for women using any HRT for 10 years or longer (1,428 cases versus 1,724 controls) revealed a protective effect of the HSD17B1_937_G allele on breast cancer risk (OR 0.86, 95 % CI: 0.73-0.99; p = 0.048). Thus, our previous finding of a protective effect of the HSD17B1_937_G allele on HRT-associated breast cancer risk has now been confirmed both in independent large patient cohorts and a comprehensive pooled analysis supporting the hypothesis that a HSD17B1-mediated decreased conversion of estrone to the more potent 17β-estradiol may reduce the estrogenic effects, thereby reducing the risk of developing breast cancer during long-term HRT use.

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.

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.

Ndossi DG, Frizzell C, Tremoen NH, et al.
An in vitro investigation of endocrine disrupting effects of trichothecenes deoxynivalenol (DON), T-2 and HT-2 toxins.
Toxicol Lett. 2012; 214(3):268-78 [PubMed] Related Publications
Trichothecenes are a large family of chemically related mycotoxins. Deoxynivalenol (DON), T-2 and HT-2 toxins belong to this family and are produced by various species of Fusarium. The H295R steroidogenesis assay, regulation of steroidogenic gene expression and reporter gene assays (RGAs) for the detection of androgen, estrogen, progestagen and glucocorticoid (ant)agonist responses, have been used to assess the endocrine disrupting activity of DON, T-2 and HT-2 toxins. H295R cells were used as a model for steroidogenesis and gene expression studies and exposed with either DON (0.1-1000ng/ml), T-2 toxin (0.0005-5ng/ml) or HT-2 toxin (0.005-50ng/ml) for 48h. We observed a reduction in hormone levels in media of exposed cells following radioimmunoassay. Cell viability was determined by four colorimetric assays and we observed reduced cell viability with increasing toxin concentrations partly explaining the significant reduction in hormone levels at the highest toxin concentration of all three trichothecenes. Thirteen of the 16 steroidogenic genes analyzed by quantitative real time PCR (RT-qPCR) were significantly regulated (P<0.05) by DON (100ng/ml), T-2 toxin (0.5ng/ml) and HT-2 toxin (5ng/ml) compared to the control, with reference genes (B2M, ATP5B and ACTB). Whereas HMGR and CYP19 were down-regulated, CYP1A1 and CYP21 were up-regulated by all three trichothecenes. DON further up-regulated CYP17, HSD3B2, CYP11B2 and CYP11B1 and down-regulated NR5A1. T-2 toxin caused down-regulation of NR0B1 and NR5A1 whereas HT-2 toxin induced up-regulation of EPHX and HSD17B1 and down-regulation of CYP11A and CYP17. The expressions of MC2R, StAR and HSD17B4 genes were not significantly affected by any of the trichothecenes in the present study. Although the results indicate that there is no evidence to suggest that DON, T-2 and HT-2 toxins directly interact with the steroid hormone receptors to cause endocrine disruption, the present findings indicate that exposure to DON, T-2 toxin and HT-2 toxin have effects on cell viability, steroidogenesis and alteration in gene expression indicating their potential as endocrine disruptors.

Aka JA, Zerradi M, Houle F, et al.
17beta-hydroxysteroid dehydrogenase type 1 modulates breast cancer protein profile and impacts cell migration.
Breast Cancer Res. 2012; 14(3):R92 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Human 17beta-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a steroid-converting enzyme that has long been known to play critical roles in estradiol synthesis and more recently in dihydrotestosterone (DHT) inactivation, showing a dual function that promotes breast cancer cell proliferation. Previously, we reported the first observation of the influence of the enzyme on endogenous estrogen-responsive gene expression. Here, we demonstrate the impact of 17β-HSD1 expression on the breast cancer cell proteome and investigate its role in cell migration.
METHODS: 17β-HSD1 was stably transfected in MCF7 cells and the proteome of the generated cells overexpressing 17β-HSD1 (MCF7-17βHSD1 cells) was compared to that of the wild type MCF7 cells. Proteomics study was performed using two-dimensional gel electrophoresis followed by mass spectrometry analysis of differentially expressed protein spots. Reverse transcription quantitative real-time PCR (RT-qPCR) was used to investigate the transcription of individual gene. The effect of 17β-HSD1 on MCF7 cell migration was verified by a wound-healing assay.
RESULTS: Proteomic data demonstrate that the expression of more than 59 proteins is modulated following 17β-HSD1 overexpression. 17β-HSD1 regulates the expression of important genes and proteins that are relevant to cell growth control, such as BRCA2 and CDKN1A interacting protein (BCCIP) and proliferating cell nuclear antigen (PCNA) which are down- and upregulated in MCF7-17βHSD1 cells, respectively. RT-qPCR data reveal that 17β-HSD1 increases the mRNA levels of estrogen receptors (ER) alpha and beta by 171 and 120%, respectively, while decreasing that of the androgen receptor by 64%. Interestingly, 17β-HSD1 increases the mRNA transcript (by 3.6 times) and the protein expression of the metastasis suppressor gene nm23-H1 and the expression of the two enzymes are closely correlated. We have further shown that 17β-HSD1 expression is associated with an increase of MCF7 cell migration.
CONCLUSIONS: In addition to the regulation of important genes, we have demonstrated for the first time that 17β-HSD1 increases breast cancer cell migration, in spite of its positive regulation of the antimetastatic gene NM23. This is also correlated to its stimulation of breast cancer cell growth, further confirming its targeting in ER positive breast cancer. The novel findings in this study suggest several directions for future research on the contribution of 17β-HSD1 to breast cancer progression and related treatment.

Cong RJ, Huang ZY, Cong L, et al.
Polymorphisms in genes HSD17B1 and HSD17B2 and uterine leiomyoma risk in Chinese women.
Arch Gynecol Obstet. 2012; 286(3):701-5 [PubMed] Related Publications
PURPOSE: To evaluate the association of HSD17B1 and HSD17B2 gene polymorphisms with uterine leiomyoma in Chinese women.
METHODS: 121 Chinese women with clinically diagnosed uterine leiomyoma and 217 healthy normal Chinese women were investigated to compare three single nucleotide polymorphisms (SNPs) (rs605059 and rs676387 of HSD17B1 gene and rs8191246 of HSD17B2 gene) by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing method.
RESULTS: All the SNPs were polymorphisms in Chinese women. Frequencies of rs605059 AA genotype and A allele were significantly increased in patients with uterine leiomyoma compared to healthy controls (GG vs. AA, OR 0.40, 95 % CI 0.20-0.82; G vs. A, OR 0.68, 95 % CI 0.50-0.94).
CONCLUSION: The results suggest that the genotype of HSD17B1 rs605059 may play a role in the tumourgenesis of uterine leiomyoma.

Reding KW, Chen C, Lowe K, et al.
Estrogen-related genes and their contribution to racial differences in breast cancer risk.
Cancer Causes Control. 2012; 23(5):671-81 [PubMed] Free Access to Full Article Related Publications
Racial differences in breast cancer risk, including the risks of hormone receptor subtypes of breast cancer, have been previously reported. We evaluated whether variation in genes related to estrogen metabolism (COMT, CYP1A1, CYP1B1, CYP17A1, CYP19A1, ESR1, GSTM1, GSTP1, GSTT1, HSD17B1, SULT1A1, and UGT1A1) contributes to breast cancer risk and/or racial differences in risk within the CARE study, a multi-centered, population-based case-control study of breast cancer. Genetic variation was assessed as single nucleotide polymorphisms (SNPs), haplotypes, and SNP-hormone therapy (HT) interactions within a subset of 1,644 cases and 1,451 controls, including 949 Black women (493 cases and 456 controls), sampled from the CARE study population. No appreciable associations with breast cancer risk were detected for single SNPs or haplotypes in women overall. We detected SNP-HT interactions in women overall within CYP1B1 (rs1800440; p (het) = 0.003) and within CYP17A1 (rs743572; p (het) = 0.009) in which never users of HT were at a decreased risk of breast cancer, while ever users were at a non-significant increased risk. When investigated among racial groups, we detected evidence of an SNP-HT interaction with CYP1B1 in White women (p value = 0.02) and with CYP17A1 in Black women (p value = 0.04). This analysis suggests that HT use may modify the effect of variation in estrogen-related genes on breast cancer risk, which may affect Black and White women to a different extent.

Cornel KM, Kruitwagen RF, Delvoux B, et al.
Overexpression of 17β-hydroxysteroid dehydrogenase type 1 increases the exposure of endometrial cancer to 17β-estradiol.
J Clin Endocrinol Metab. 2012; 97(4):E591-601 [PubMed] Related Publications
CONTEXT: The local interconversions between estrone (low activity) and 17β-estradiol (potent compound) by 17β-hydroxysteroid dehydrogenases (17β-HSDs) can lead to high 17β-estradiol generation in endometrial cancer (EC).
OBJECTIVE: Examine the balance between the 17β-HSDs reducing estrone to 17β-estradiol (types 1, 5, 12, and 7) and those oxidizing 17β-estradiol to estrone (2, 4, and 8), in EC.
PATIENTS AND METHODS: Reducing and oxidizing 17β-HSD activities (HPLC) and mRNA level (RT-PCR) were assessed in normal post-menopausal (n = 16), peritumoral endometrium (normal tissue beside cancer, n = 13), and 58 EC (29 grade 1, 18 grade 2, 11 grade 3).
RESULTS: Grade 1 EC displayed a shifted estrone reduction/17β-estradiol oxidation balance in favor of 17β-estradiol compared with controls. This was more pronounced among estrogen receptor-α (ER-α)-positive biopsies. Type 1 17β-HSD mRNA (HSD17B1 gene expression, real time PCR) and protein levels (immunohistochemistry) were higher in ER-α-positive grade 1 EC than controls. The mRNA coding for types 4, 5, 7, 8, and 12 17β-HSD did not vary, whereas that coding for type 2 17β-HSD was increased in high-grade lesions compared with controls. Three-dimensional ex vivo EC explant cultures demonstrated that 17β-HSD type 1 generated 17β-estradiol from estrone and increased tumor cell proliferation. Additional in vitro studies using EC cells confirmed that in the presence of 17β-HSD type 1, estrone induced estrogen signaling activation similarly to 17β-estradiol. Therefore, estrone was reduced to 17β-estradiol.
CONCLUSIONS: Type 1 17β-HSD increases 17β-estradiol exposure in grade 1 EC, thus supporting tumor growth. This enzyme represents a potential therapeutic target.

Audet-Walsh É, Bellemare J, Lacombe L, et al.
The impact of germline genetic variations in hydroxysteroid (17-beta) dehydrogenases on prostate cancer outcomes after prostatectomy.
Eur Urol. 2012; 62(1):88-96 [PubMed] Related Publications
BACKGROUND: The relationship between polymorphisms in the hydroxysteroid (17-beta) dehydrogenase (HSD17B) family of genes, which are involved in steroid hormone biotransformation, and the risk of prostate cancer (PCa) progression remains unexplored.
OBJECTIVE: Determine whether inherited variations in HSD17B genes are associated with PCa progression.
DESIGN, SETTING, AND PARTICIPANTS: We studied two independent Caucasian cohorts composed of 526 men with organ-confined PCa and 213 men with advanced disease who had a median follow-up of 7.4 yr and 7.8 yr after surgery, respectively.
MEASUREMENTS: Patients with localised PCa were genotyped for 88 haplotype-tagging single nucleotide polymorphisms in HSD17B type 1 (HSD17B1), type 2 (HSD17B2), type 3 (HSD17B3), type 4 (HSD17B4), type 5 (HSD17B5), and type 12 (HSD17B12), and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings were then investigated in advanced disease.
RESULTS AND LIMITATIONS: After adjusting for known risk factors, 12 SNPs distributed across HSD17B2, HSD17B3, and HSD17B12 were significantly associated with risk of biochemical recurrence (BCR) in localised PCa (for variants in HSD17B2: hazard ratio [HR]: 1.92-2.93; p=0.025-0.004). In addition, four variants of HSD17B2 (rs1364287, rs2955162, rs1119933, rs9934209) were significantly associated with progression-free survival (HR: 2.96-4.69; p=0.004-0.00005) and overall survival in advanced disease (HR: 3.98-8.14; p=0.003-0.00002). Four variants of HSD17B3 and HSD17B12 were associated with a reduced risk of BCR (HR: 0.51-0.65; p=0.020-0.036) but not with progression in advanced disease. These results were generated mainly in Caucasians and should be studied in other ethnic groups.
CONCLUSIONS: This study suggests a prominent role for common genetic variants in the HSD17B2 pathway in PCa progression.

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.

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