Research IndicatorsGraph generated 11 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 11 March, 2017 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: HSD17B1 (cancer-related)
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
] 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.
Takagi M, Miki Y, Miyashita M, et al.Intratumoral estrogen production and actions in luminal A type invasive lobular and ductal carcinomas.
Breast Cancer Res Treat. 2016; 156(1):45-55 [PubMed
] Related Publications
The great majority of invasive lobular carcinoma (ILC) is estrogen-dependent luminal A type carcinoma but the details of estrogen actions and its intratumoral metabolism have not been well studied compared to invasive ductal carcinoma (IDC). We first immunolocalized estrogen-related enzymes including estrogen sulfotransferase (EST), estrogen sulfatase (STS), 17β-hydroxysteroid dehydrogenase (HSD) 1/2, and aromatase. We then evaluated the tissue concentrations of estrogens in ILC and IDC and subsequently estrogen-responsive gene profiles in these tumors in order to explore the possible differences and/or similarity of intratumoral estrogen environment of these two breast cancer subtypes. The status of STS and 17βHSD1 was significantly lower in ILCs than IDCs (p = 0.022 and p < 0.0001), but that of EST and 17βHSD2 vice versa (p < 0.0001 and p = 0.0106). In ILCs, tissue concentrations of estrone and estradiol were lower than those in IDCs (p = 0.0709 and 0.069). In addition, the great majority of estrogen response genes tended to be lower in ILCs. Among those genes above, FOXP1 was significantly higher in ILCs than in IDCs (p = 0.002). FOXP1 expression was reported to be significantly higher in relapse-free IDC patients treated with tamoxifen. Therefore, tamoxifen may be considered an option of endocrine therapy for luminal A type ILC patients. This is the first study to demonstrate the detailed and comprehensive status of intratumoral production and metabolism of estrogens and the status of estrogen response genes in luminal A-like ILC with comparison to those in luminal A-like IDCs.
Shi L, Yang X, Dong X, Zhang BPolymorphism 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.
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.
Lee YE, He HL, Shiue YL, et al.The prognostic impact of lipid biosynthesis-associated markers, HSD17B2 and HMGCS2, in rectal cancer treated with neoadjuvant concurrent chemoradiotherapy.
Tumour Biol. 2015; 36(10):7675-83 [PubMed
] Related Publications
Neoadjuvant concurrent chemoradiotherapy has been widely used for rectal cancer to improve local tumor control. The varied response of individual tumors encouraged us to search for useful biomarkers to predict the therapeutic response. The study was aimed to evaluate the prognostic impact of lipid biosynthesis-associated biomarkers in rectal cancer patients treated with preoperative chemoradiotherapy. Through analysis of the previously published gene expression profiling database focusing on genes associated with lipid biosynthesis, we found that HSD17B2 and HMGCS2 were the top two significantly upregulated genes in the non-responders. We further evaluated their expression by immunohistochemistry in the pre-treatment tumor specimens from 172 patients with rectal cancer and statistically analyzed the associations between their expression and various clinicopathological factors, as well as survival. High expression of HMGCS2 or HSD17B2 was significantly associated with advanced pre- and post-treatment tumor or nodal status (P < 0.001) and lower tumor regression grade (P < 0.001). More importantly, high expression of either HMGCS2 or HSD17B2 was of prognostic significance, with HMGCS2 overexpression indicating poor prognosis for disease-free survival (P = 0.0003), local recurrence-free survival (P = 0.0115), and metastasis-free survival (P = 0.0119), while HSD17B2 overexpression was associated with poor prognosis for disease-free survival (P <0.0001), local recurrence-free survival (P = 0.0009), and metastasis-free survival (P < 0.0001). In multivariate analysis, only HSD17B2 overexpression remained as an independent prognosticator for shorter disease-free survival (P < 0.001) and metastasis-free survival (P = 0.008). In conclusion, high expression of either HSD17B2 or HMGCS2 predicted poor susceptibility of rectal cancer to preoperative chemoradiotherapy. Both acted as promising prognostic factors, particularly HSD17B2.
Epithelial ovarian cancer (EOC) accounts for about 90% of malignant ovarian tumors, and estrogen is often implicated in disease progression. We therefore compared the potential for gating of estrogen action via pre-receptor metabolism in normal human ovarian surface epithelium (OSE), EOC and selected EOC cell lines (SKOV3 and PEO1). Steroid sulphatase (STS), estrogen sulfotransferase (EST), 17β-hydroxysteroid dehydrogenases 2 (17BHSD2) and 5 (17BHSD5) mRNAs, proteins and enzymatic activities were all detectable in primary cell cultures of OSE and EOC, whereas aromatase and 17BHSD1 expression was negligible. qRT-PCR assay on total mRNA revealed significantly higher EST mRNA expression in OSE compared to EOC (P<0.05). Radioenzymatic measurements confirmed reduced sulfoconjugation (neutralization) of free estrogen in EOC relative to OSE. OSE cells were more effective at converting free [(3)H]-E1 to [(3)H]-E1S or [(3)H]-E2S, while EOC cell lines mainly converted [(3)H]-E1 to [(3)H]-E2 with minimal formation of [(3)H]-E1S or [(3)H]-E2S. IL1α treatment suppressed EST (P<0.01) and 17BHSD2 (P<0.001) mRNA levels in OSE and stimulated STS mRNA levels (P<0.001) in cancer (SKOV3) cells. These results show that estrogen is differentially metabolized in OSE and EOC cells, with E2 'activation' from conjugated estrogen predominating in EOC. Inflammatory cytokines may further augment the local production of E2 by stimulating STS and suppressing EST. We conclude that local estrogen metabolism may be a target for EOC treatment.
Fokidis HB, Yieng Chin M, Ho VW, et al.A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.
J Steroid Biochem Mol Biol. 2015; 150:35-45 [PubMed
] Related Publications
Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are likely to be mechanistic drivers behind the observed tumor growth suppression.
Frycz BA, Murawa D, Borejsza-Wysocki M, et al.Expression of 17β-hydroxysteroid dehydrogenase type 2 is associated with some clinicopathological features in gastric cancer.
Biomed Pharmacother. 2015; 70:24-7 [PubMed
] Related Publications
In most populations, gastric cancer (GC) incidence is higher in men than in women, which may suggest the role of sex steroid hormones in gastric cancerogenesis. Both, androgens and estrogens can be synthetised in peripherial tissues. This process is controlled by expression of steroidogenic enzymes. Therefore, we evaluate the 17β-hydroxysteroid dehydrogenase type 2 (HSD17B2) transcript and protein levels in gastric tumoral and nontumoral tissue. We also determined the association between HSD17B2 transcript and protein levels and some clinicopathological features in GC. We found significantly decreased levels of HSD17B2 transcript (P=0.00072) and protein (P=0.00017) in primary tumoral tissues of GC patients, as compared to nontumoral tissues. In patients above 60 years of age the amounts of HSD17B2 transcript (P=0.00044) and protein (P=0.00027) were significantly lower in tumoral than nontumoral tissues. Similarly, lower HSD17B2 levels, both in terms of the transcript and protein, were observed in tumoral tissues of male (P=0.013, P=0.0014), patients stomach (P=0.0062, P=0.045) and cardia (P=0.02, P=0.02) site of tumor, T3 (P=0.018, P=0.014) depth of invasion, N0 (P=0.017, P=0.045) lymph node metastasis, G3 (P=0.0027, P=0.014) malignancy grade. We also observed significantly reduced level of HSD17B2 transcript in tumoral tissue specimens of females (P=0.014), T4 depth of invasion (P=0.02), N3 lymph node metastasis (P=0.037) and G2 malignancy grade (P=0.045). Furthermore, diffuse GC histological types were associated with lower HSD17B2 protein level (P=0.024) than nontumoral tissues. We demonstrated that HSD17B2 transcript and protein levels are linked to some clinicopathological features in GC.
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 TLThe 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.
Fankhauser M, Tan Y, Macintyre G, et al.Canonical androstenedione reduction is the predominant source of signaling androgens in hormone-refractory prostate cancer.
Clin Cancer Res. 2014; 20(21):5547-57 [PubMed
] Related Publications
PURPOSE: It has been recognized for almost a decade that concentrations of signaling androgens sufficient to activate the androgen receptor are present in castration-resistant prostate cancer tissue. The source of these androgens is highly controversial, with three competing models proposed. We, therefore, wished to determine the androgenic potential of human benign and malignant (hormone-naïve and treated) prostate tissue when incubated with various precursors and examine concomitant changes in enzyme expression.
EXPERIMENTAL DESIGN: Freshly harvested prostate tissue [benign, hormone-naïve, and hormone-refractory prostate cancer (HRPC)] was incubated in excess concentrations of cholesterol, progesterone, DHEA, androstenedione, or testosterone for 96 hours, and steroid concentrations in the conditioned media measured by gas chromatography-mass spectroscopy. Changes in the expression of androgen synthetic and/or degradative enzymes were determined by expression microarray and qPCR. Significant changes were confirmed in an independent dataset.
RESULTS: Of the precursor molecules tested, only incubation with androstenedione gave rise to significant concentrations of signaling androgens. Although this was observed in all tissue types, it occurred to a significantly greater degree in hormone-refractory compared with hormone-naïve cancer. Consistent with this, gene set enrichment analysis of the expression microarray data revealed significant upregulation of 17HSD17B activity, with overexpression of the canonical enzyme AKR1C3 confirmed by qPCR in the same samples and in a publicly available expression dataset. Importantly, we found no evidence to support a significant contribution from either the "backdoor" or "5-α dione" pathway.
CONCLUSIONS: Reduction of androstenedione to testosterone by the canonical HSD17B AKR1C3 is the predominant source of signaling androgens in HRPC.
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.
Straume AH, Knappskog S, Lønning PEEffects of SNP variants in the 17β-HSD2 and 17β-HSD7 genes and 17β-HSD7 copy number on gene transcript and estradiol levels in breast cancer tissue.
J Steroid Biochem Mol Biol. 2014; 143:192-8 [PubMed
] Related Publications
Breast cancers reveal elevated E2 levels compared to plasma and normal breast tissue. Previously, we reported intra-tumour E2 to be negatively correlated to transcription levels of 17β-HSD2 but positively correlated to 17β-HSD7. Here, we explored these mechanisms further by analysing the same breast tumours for 17β-HSD2 and -7 SNPs, as well as 17β-HSD7 gene copy number. Among the SNPs detected, we found the 17β-HSD2 rs4445895_T allele to be associated with lower intra-tumour mRNA (p=0.039) and an elevated intra-tumour E2 level (p=0.006). In contrast, we found the 17β-HSD7 rs1704754_C allele to be associated with elevated mRNA (p=0.050) but not to E2 levels in breast tumour tissue. Surprisingly, 17β-HSD7 - gene copy number was elevated in 19 out of 46 breast tumours examined. Elevated copy number was associated with an increased mRNA expression level (p=0.013) and elevated tumour E2 (p=0.025). Interestingly, elevated 17β-HSD7 - gene copy number was associated with increased expression not only of 17β-HSD7, but the 17β-HSD7_II pseudogene as well (p=0.019). Expression level of 17β-HSD7 and its pseudogene was significantly correlated both in tumour tissue (rs=0.457, p=0.001) and in normal tissue (rs=0.453, p=0.002). While in vitro transfection experiments revealed no direct impact of 17β-HSD7 expression on pseudogene level, the fact that 17β-HSD7 and 17β-HSD7_II share a 95.6% sequence identity suggests the two transcripts may be subject to common regulatory mechanisms. In conclusion, genetic variants of 17β-HSD2 and 17β-HSD7 may affect intra-tumour gene expression as well as breast cancer E2 levels in postmenopausal women.
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.
Aromatase inhibitors (AIs) are the most effective class of drugs in the endocrine treatment of breast cancer, with an approximate 50% treatment response rate. Our objective was to determine whether intratumoral expression levels of estrogen-related genes are predictive of AI responsiveness in postmenopausal women with breast cancer. Primary breast carcinomas were obtained from 112 women who received AI therapy after failing adjuvant tamoxifen therapy and developing recurrent breast cancer. Tumor ERα and PR protein expression were analyzed by immunohistochemistry (IHC). Messenger RNA (mRNA) levels of 5 estrogen-related genes-AKR1C3, aromatase, ERα, and 2 estradiol/ERα target genes, BRCA1 and PR-were measured by real-time PCR. Tumor protein and mRNA levels were compared with breast cancer progression rates to determine predictive accuracy. Responsiveness to AI therapy-defined as the combined complete response, partial response, and stable disease rates for at least 6 months-was 51%; rates were 56% in ERα-IHC-positive and 14% in ERα-IHC-negative tumors. Levels of ERα, PR, or BRCA1 mRNA were independently predictive for responsiveness to AI. In cross-validated analyses, a combined measurement of tumor ERα and PR mRNA levels yielded a more superior specificity (36%) and identical sensitivity (96%) to the current clinical practice (ERα/PR-IHC). In patients with ERα/PR-IHC-negative tumors, analysis of mRNA expression revealed either non-significant trends or statistically significant positive predictive values for AI responsiveness. In conclusion, expression levels of estrogen-related mRNAs are predictive for AI responsiveness in postmenopausal women with breast cancer, and mRNA expression analysis may improve patient selection.
Ofude M, Mizokami A, Kumaki M, et al.Repression of cell proliferation and androgen receptor activity in prostate cancer cells by 2'-hydroxyflavanone.
Anticancer Res. 2013; 33(10):4453-61 [PubMed
] Related Publications
BACKGROUND: Prevention of the development of castration-resistant from hormone-naïve prostate cancer is an important issue in maintaining the quality of life of the patients. We explored the effect of 2'-hydroxyflavanone on proliferation and androgen responsiveness using prostate cancer cell lines.
MATERIALS AND METHODS: To investigate the effect of 2'-hydroxyflavanone on proliferation, prostate cancer cells were treated with 2'-hydroxyflavanone. Androgen-responsiveness in LNCaP cells was confirmed by luciferase assay after transfection of luciferase reporter driven by prostate specific antigen promoter. To detect androgen receptor (AR) expression, reverse transcriptase polymerase chain reaction and western blot analysis were conducted.
RESULTS: 2'-Hydroxyflavanone inhibited the proliferation of PC-3 and DU145 cells by induction of apoptosis. 2'-Hydroxyflavanone inhibited the proliferation of LNCaP cells stimulated by androgens and attenuated androgen-responsiveness through down-regulation of AR protein.
CONCLUSION: 2'-Hydroxyflavanone not only inhibited proliferation of prostate cancer cells, but also repressed androgen-responsiveness, suggesting that it might be a useful agent in preventing recurrence of prostate cancer.
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.
Sung CH, Im HJ, Park N, et al.Induction of steroid sulfatase expression in PC-3 human prostate cancer cells by insulin-like growth factor II.
Toxicol Lett. 2013; 223(2):109-15 [PubMed
] Related Publications
Human steroid sulfatase (STS) plays an important role in regulating the formation of biologically active estrogens and may be a promising target for treating estrogen-mediated carcinogenesis. The molecular mechanism of STS gene expression, however, is still not clear. Growth factors are known to increase STS activity but the changes in STS expression have not been completely understood. To determine whether insulin-like growth factor (IGF)-II can induce STS gene expression, the effects of IGF-II on STS expression were studied in PC-3 human prostate cancer cells. RT-PCR and Western blot analysis showed that IGF-II treatment significantly increased the expression of STS mRNA and protein in concentration- and time-dependent manners. To understand the signaling pathway by which IGF-II induces STS gene expression, the effects of specific PI3-kinase/Akt and NF-κB inhibitors were determined. When the cells were treated with IGF-II and PI3-kinase/Akt inhibitors, such as LY294002, wortmannin, or Akt inhibitor IV, STS expression induced by IGF-II was significantly blocked. Moreover, we found that NF-κB inhibitors, such as MG-132, bortezomib, Bay 11-7082 or Nemo binding domain (NBD) binding peptide, also strongly prevented IGF-II from inducing STS gene expression. We assessed whether IGF-II activates STS promoter activity using transient transfection with a luciferase reporter. IGF-II significantly stimulated STS reporter activity. Furthermore, IGF-II induced expression of 17β-hydroxysteroid dehydrogenase (HSD) 1 and 3, whereas it reduced estrone sulfotransferase (EST) gene expression, causing enhanced estrone and β-estradiol production. Taken together, these results strongly suggest that IGF-II induces STS expression via a PI3-kinase/Akt-NF-κB signaling pathway in PC-3 cells and may induce estrogen production and estrogen-mediated carcinogenesis.
Rižner TLEstrogen biosynthesis, phase I and phase II metabolism, and action in endometrial cancer.
Mol Cell Endocrinol. 2013; 381(1-2):124-39 [PubMed
] Related Publications
Endometrial cancer is the most common gynecological malignancy in the developed World. Based on their histopathology, clinical manifestation, and epidemiology, the majority of endometrial cancer cases can be divided into two groups: the more prevalent type 1 which is associated with unopposed estrogen exposure; and the less common type 2, which is usually not associated with hyper-estrogenic factors. This manuscript overviews the published data on the expression of genes encoding the estrogen biosynthetic enzymes, the phase I and phase II estrogen metabolic enzymes, and the estrogen receptors in endometrial cancer, at the mRNA, protein and enzyme activity levels. The potential role of altered expression of these enzymes and receptors in cancerous versus control endometrial tissue, and the implication of estrogens in tumor initiation and promotion, are discussed. Finally, based on the published data, a model of estrogen metabolism and actions is proposed for pre-cancerous and cancerous endometrial tissue, and the role of the estrogens in the progression of endometrial cancer from endometrial hyperplasia is suggested.
Piao YS, Wiesenfeld P, Sprando R, Arnold JTTGFβ1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment?
J Steroid Biochem Mol Biol. 2013; 138:206-13 [PubMed
] Free Access to Full Article Related Publications
The inflammatory tissue microenvironment can be an active promoter in preneoplastic cancer lesions. Altered steroid hormone metabolism as induced by the inflammatory microenvironment may contribute to epithelial cancer progression. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant endogenous steroid hormone present in human serum and can be metabolized to DHEA, androgens and/or estrogens in peripheral tissues. We have previously reported that TGFβ1-induced reactive prostate stromal cells increase DHEA metabolism to active androgens and alter prostate cancer cell gene expression. While much of the focus on mechanisms of prostate cancer and steroid metabolism is in the epithelial cancer cells, this study focuses on TGFβ1-induced effects on DHEA metabolic pathways and enzymes in human prostate stromal cells. In DHEA-treated primary prostate stromal cells, TGFβ1 produced time- and dose-dependent increases in metabolism of DHEA to androstenedione and testosterone. Also TGFβ1-treated prostate stromal cells exhibited changes in the gene expression of enzymes involved in steroid metabolism including up-regulation of 3β hydroxysteroid dehydrogenase (HSD), and down-regulation of 17βHSD5, and 17βHSD2. These studies suggest that reactive prostate stroma and the inflammatory microenvironment may contribute to altered steroid metabolism and increased intratumoral androgens.
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 MThe 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.
Sinreih M, Hevir N, Rižner TLAltered 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.
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.
Takagi K, Moriya T, Kurosumi M, et al.Intratumoral estrogen concentration and expression of estrogen-induced genes in male breast carcinoma: comparison with female breast carcinoma.
Horm Cancer. 2013; 4(1):1-11 [PubMed
] Related Publications
It is speculated that estrogens play important roles in the male breast carcinoma (MBC) as well as the female breast carcinoma (FBC). However, estrogen concentrations or molecular features of estrogen actions have not been reported in MBC, and biological significance of estrogens remains largely unclear in MBC. Therefore, we examined intratumoral estrogen concentrations, estrogen receptor (ER) α/ERβ status, and expression profiles of estrogen-induced genes in MBC tissues, and compared these with FBC. 17β-Estradiol concentration in MBC (n = 4) was significantly (14-fold) higher than that in non-neoplastic male breast (n = 3) and tended to be higher than that in FBC (n = 7). Results of microarray analysis clearly demonstrated that expression profiles of the two gene lists, which were previously reported as estrogen-induced genes in MCF-7 breast carcinoma cell line, were markedly different between MBC and FBC. In the immunohistochemistry, MBC tissues were frequently positive for aromatase (63 %) and 17β-hydroxysteroid dehydrogenase type 1 (67 %), but not for steroid sulfatase (6.7 %). A great majority (77 %) of MBC showed positive for both ERα and ERβ, and its frequency was significantly higher than FBC cases. These results suggest that estradiol is locally produced in MBC tissue by aromatase. Different expression profiles of the estrogen-induced genes may associate with different estrogen functions in MBC from FBC, which may be partly due to their ERα/ERβ status.
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.
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.