SHBG

Gene Summary

Gene:SHBG; sex hormone-binding globulin
Aliases: ABP, SBP, TEBG
Location:17p13.1
Summary:This gene encodes a steroid binding protein that was first described as a plasma protein secreted by the liver but is now thought to participate in the regulation of steroid responses. The encoded protein transports androgens and estrogens in the blood, binding each steroid molecule as a dimer formed from identical or nearly identical monomers. Polymorphisms in this gene have been associated with polycystic ovary syndrome and type 2 diabetes mellitus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:sex hormone-binding globulin
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

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

  • Cervical Cancer
  • Exons
  • Haplotypes
  • Cohort Studies
  • Estradiol
  • Estrogens
  • Sex Hormone-Binding Globulin
  • Polymorphism
  • Cancer Gene Expression Regulation
  • Base Sequence
  • Adolescents
  • Odds Ratio
  • Gonadal Steroid Hormones
  • Androgens
  • Luteinizing Hormone
  • Breast Cancer
  • Polymerase Chain Reaction
  • Case-Control Studies
  • Insulin-Like Growth Factor I
  • Alleles
  • Messenger RNA
  • Siblings
  • Genotype
  • Single Nucleotide Polymorphism
  • Blood Glucose
  • Androgen Receptors
  • Genetic Variation
  • Phenotype
  • Body Mass Index
  • Tamoxifen
  • Hyperandrogenism
  • Chromosome 17
  • Risk Factors
  • Prostate Cancer
  • Insulin
  • Utah
  • European Continental Ancestry Group
  • Insulin Resistance
  • Postmenopause
  • Genetic Predisposition
  • Genetic Association Studies
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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

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

Latest Publications: SHBG (cancer-related)

van Kruchten M, de Vries EF, Arts HJ, et al.
Assessment of estrogen receptor expression in epithelial ovarian cancer patients using 16α-18F-fluoro-17β-estradiol PET/CT.
J Nucl Med. 2015; 56(1):50-5 [PubMed] Related Publications
UNLABELLED: The estrogen receptor α (ERα) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ERα expression with the tracer 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of (18)F-FES PET to determine tumor ERα expression noninvasively in epithelial ovarian cancer patients.
METHODS: (18)F-FES PET/CT was performed shortly before cytoreductive surgery. Tumor (18)F-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. (18)F-FES PET/CT findings were compared with histology and immunohistochemistry for ERα, ERβ, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells × staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis.
RESULTS: In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor (18)F-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative (18)F-FES uptake correlated with the semiquantitative immunoscore for ERα (ρ = 0.65, P < 0.01) and weakly with progesterone receptor expression (ρ = 0.46, P = 0.03) and was not associated with ERβ expression (ρ = 0.21, P = 0.33). The optimum threshold to discriminate ERα-positive and ERα-negative lesions was a maximum standardized uptake value greater than 1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% confidence interval, 0.70-1.00). In 2 of 7 patients with cytology/histology available at primary diagnosis and at debulking surgery, immunohistochemical ERα expression had changed over time. (18)F-FES PET was in accordance with histology at debulking surgery but not at primary diagnosis, indicating that (18)F-FES PET could provide reliable information about current tumor ERα status.
CONCLUSION: (18)F-FES PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases noninvasively. Evaluation of the predictive value of (18)F-FES PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted.

Schmidt S, Liu G, Liu G, et al.
Enhanced Orai1 and STIM1 expression as well as store operated Ca2+ entry in therapy resistant ovary carcinoma cells.
Oncotarget. 2014; 5(13):4799-810 [PubMed] Free Access to Full Article Related Publications
Mechanisms underlying therapy resistance of tumor cells include protein kinase Akt. Putative Akt targets include store-operated Ca(2+)-entry (SOCE) accomplished by pore forming ion channel unit Orai1 and its regulator STIM1. We explored whether therapy resistant (A2780cis) differ from therapy sensitive (A2780) ovary carcinoma cells in Akt, Orai1, and STIM1 expression, Ca(2+)-signaling and cell survival following cisplatin (100 µM) treatment. Transcript levels were quantified with RT-PCR, protein abundance with Western blotting, cytosolic Ca(2+)-activity ([Ca(2+)]i) with Fura-2-fluorescence, SOCE from increase of [Ca(2+)]i following Ca(2+)-readdition after Ca(2+)-store depletion, and apoptosis utilizing flow cytometry. Transcript levels of Orai1 and STIM1, protein expression of Orai1, STIM1, and phosphorylated Akt, as well as SOCE were significantly higher in A2780cis than A2780 cells. SOCE was decreased by Akt inhibitor III (SH-6, 10 µM) in A2780cis but not A2780 cells and decreased in both cell lines by Orai1 inhibitor 2-aminoethoxydiphenyl borate (2-ABP, 50 µM). Phosphatidylserine exposure and late apoptosis following cisplatin treatment were significantly lower in A2780cis than A2780 cells, a difference virtually abolished by SH-6 or 2-ABP. In conclusion, Orai1/STIM1 expression and function are increased in therapy resistant ovary carcinoma cells, a property at least in part due to enhanced Akt activity and contributing to therapy resistance in those cells.

Singer CF, Bennink HJ, Natter C, et al.
Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer.
Carcinogenesis. 2014; 35(11):2447-51 [PubMed] Related Publications
Estetrol (E4) is a fetal estrogen with estrogenic effects on reproductive organs and bone in preclinical models and in postmenopausal women. However, E4 exerts antiestrogenic effects on breast cancer (BC) cell growth in vitro and in vivo. We have investigated the effect of 14 days preoperative treatment with 20mg E4 per day on tumor proliferation markers, sex steroid receptor expression and endocrine parameters in a prospective, randomized, placebo-controlled, preoperative window trial in 30 pre- and post-menopausal women with estrogen-receptor positive early BC. E4 had a significant pro-apoptotic effect on tumor tissue, whereas Ki67 expression remained unchanged in both pre- and post-menopausal women. E4 increased sex-hormone-binding globulin significantly thereby reducing the concentrations of bioavailable estradiol. Follicle-stimulating hormone levels decreased in postmenopausal women only and luteinizing hormone levels remained unchanged. Systemic insulin growth factor-1 levels decreased significantly. Intratumoral epithelial ERα expression decreased significantly and a trend was found towards an increased expression of ERβ. This clinical data support the preclinical findings that E4 has antiestrogenic effects on BC cells, whereas earlier studies have shown that E4 has estrogenic effects on reproductive tissues and bone. Further clinical studies seem acceptable and are needed to confirm the safety and efficacy of E4 for the breast in hormone replacement therapy, including hormone replacement therapy in women who have or have had BC, especially in those BC patients treated with aromatase inhibitors and suffering from serious complaints due to estrogen deficiency.

Lim VW, Lim WY, Zhang Z, et al.
Serum estrogen receptor beta mediated bioactivity correlates with poor outcome in lung cancer patients.
Lung Cancer. 2014; 85(2):293-8 [PubMed] Related Publications
OBJECTIVES: The role of estrogen signaling in lung cancer remains unresolved. We investigate the influence of serum estrogenic compounds and estrogen receptor (ERα and ERβ) mediated bioactivity on lung cancer outcomes.
MATERIALS AND METHODS: Serum samples were collected from 222 postmenopausal Chinese patients diagnosed with lung cancer in five Singapore hospitals. Levels of the estrogenic compounds estradiol and estrone were measured using liquid chromatography tandem mass spectrometry. Free estradiol levels were calculated based on sex hormone binding globulin levels. ERα- and ERβ-mediated bioactivity in serum samples were analyzed using reporter gene bioassays in human cells.
RESULTS AND CONCLUSION: High ERβ-mediated bioactivity predicted poorer lung cancer survival (p=0.001) on multivariable Cox regression analysis with adjustment for age, stage of tumor, smoking status, body mass index and histology. In comparison, levels of estrogens and ERα-mediated bioactivity were not associated with prognosis. Compared to the lowest tertile of ERβ-mediated bioactivity, patients in the middle and highest tertiles had HR (95%CI) 1.60 (1.10-2.33) and 1.93 (1.32-2.82) (p for trend=0.001) higher risk of death from lung cancer. Using Kaplan-Meier survival curves, patients with high ERβ-mediated bioactivity correlated with poorer overall survival (p=0.033). ERβ-mediated bioactivity did not differ in terms of age, use of hormone replacement therapy, smoking, stage of tumor or histological subtype. High ERβ-mediated bioactivity levels in patients' serum were associated with poorer prognosis in lung cancer patients. Our findings suggest that that compound(s) other than endogenous estrogens may be exerting this ERβ bioactivity and studies to identify these compounds or groups of compounds need to be performed. Furthermore, the measurement of ERβ activity in sera could potentially serve as a prognostic marker to predict lung cancer survival, and selective blockage of ERβ signaling may have a role in lung cancer therapy.

Kim HA, Nam K, Kim SW
Tumor targeting RGD conjugated bio-reducible polymer for VEGF siRNA expressing plasmid delivery.
Biomaterials. 2014; 35(26):7543-52 [PubMed] Free Access to Full Article Related Publications
Targeted delivery of therapeutic genes to the tumor site is critical for successful and safe cancer gene therapy. The arginine grafted bio-reducible poly (cystamine bisacrylamide-diaminohexane, CBA-DAH) polymer (ABP) conjugated poly (amido amine) (PAMAM), PAM-ABP (PA) was designed previously as an efficient gene delivery carrier. To achieve high efficacy in cancer selective delivery, we developed the tumor targeting bio-reducible polymer, PA-PEG1k-RGD, by conjugating cyclic RGDfC (RGD) peptides, which bind αvβ3/5 integrins, to the PAM-ABP using polyethylene glycol (PEG, 1 kDa) as a spacer. Physical characterization showed nanocomplex formation with bio-reducible properties between PA-PEG1k-RGD and plasmid DNA (pDNA). In transfection assays, PA-PEG1k-RGD showed significantly higher transfection efficiency in comparison with PAM-ABP or PA-PEG1k-RAD in αvβ3/5 positive MCF7 breast cancer and PANC-1 pancreatic cancer cells. The targeting ability of PA-PEG1k-RGD was further established using a competition assay. To confirm the therapeutic effect, the VEGF siRNA expressing plasmid was constructed and then delivered into cancer cells using PA-PEG1k-RGD. PA-PEG1k-RGD showed 20-59% higher cellular uptake rate into MCF7 and PANC-1 than that of non-targeted polymers. In addition, MCF7 and PANC-1 cancer cells transfected with PA-PEG1k-RGD/pshVEGF complexes had significantly decreased VEGF gene expression (51-71%) and cancer cell viability (35-43%) compared with control. These results demonstrate that a tumor targeting bio-reducible polymer with an anti-angiogenic therapeutic gene could be used for efficient and safe cancer gene therapy.

Suguro M, Yoshida N, Umino A, et al.
Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis.
Cancer Sci. 2014; 105(7):897-904 [PubMed] Related Publications
Clonal heterogeneity in lymphoid malignancies has been recently reported in adult T-cell lymphoma/leukemia, peripheral T-cell lymphoma, not otherwise specified, and mantle cell lymphoma. Our analysis was extended to other types of lymphoma including marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma. To determine the presence of clonal heterogeneity, 332 cases were examined using array comparative genomic hybridization analysis. Results showed that incidence of clonal heterogeneity varied from 25% to 69% among different types of lymphoma. Survival analysis revealed that mantle cell lymphoma and diffuse large B-cell lymphoma with clonal heterogeneity showed significantly poorer prognosis, and that clonal heterogeneity was confirmed as an independent predictor of poor prognosis for both types of lymphoma. Interestingly, 8q24.1 (MYC) gain, 9p21.3 (CDKN2A/2B) loss and 17p13 (TP53, ATP1B2, SAT2, SHBG) loss were recurrent genomic lesions among various types of lymphoma with clonal heterogeneity, suggesting at least in part that alterations of these genes may play a role in clonal heterogeneity.

Florinas S, Kim J, Nam K, et al.
Ultrasound-assisted siRNA delivery via arginine-grafted bioreducible polymer and microbubbles targeting VEGF for ovarian cancer treatment.
J Control Release. 2014; 183:1-8 [PubMed] Free Access to Full Article Related Publications
The major drawback hampering siRNA therapies from being more widely accepted in clinical practice is its insufficient accumulation at the target site mainly due to poor cellular uptake and rapid degradation in serum. Therefore, we designed a novel polymeric siRNA carrier system, which would withstand serum-containing environments and tested its performance in vitro as well as in vivo. Delivering siRNA with a system combining an arginine-grafted bioreducible polymer (ABP), microbubbles (MBs), and ultrasound technology (US) we were able to synergize the advantages each delivery system owns individually, and created our innovative siRNA-ABP-MB (SAM) complexes. SAM complexes show significantly higher siRNA uptake and VEGF protein knockdown in vitro with serum-containing media when compared to naked siRNA, and 25k-branched-polyethylenimine (bPEI) representing the current standard in nonviral gene therapy. SAM complexes activated by US are also able to improve siRNA uptake in tumor tissue resulting in decelerating tumor growth in vivo.

Maciel GA, Moreira RP, Bugano DD, et al.
Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in polycystic ovary syndrome.
Clinics (Sao Paulo). 2014; 69(3):179-84 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1) polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome.
METHOD: Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests.
RESULTS: Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles, respectively. BclI carriers presented a lower frequency of insulin resistance compared with wild-type subjects.
CONCLUSION: The BclI variant is associated with a lower frequency of insulin resistance in women with polycystic ovary syndrome. Glucocorticoid gene polymorphism screening during treatment of the syndrome may be useful for identifying subgroups of at-risk patients who would benefit the most from personalized treatment.

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.

Lam UD, Lerchbaum E, Schweighofer N, et al.
Association of MEP1A gene variants with insulin metabolism in central European women with polycystic ovary syndrome.
Gene. 2014; 537(2):245-52 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) shows not only hyperandrogenemia, hirsutism and fertility problems, but also metabolic disturbances including obesity, cardiovascular events and type-2 diabetes. Accumulating evidence suggests some degree of inflammation associated with prominent aspects of PCOS. We aimed to investigate the association of genetic variants 3'UTR rs17468190 (G/T) of the inflammation-associated gene MEP1A (GenBank ID: NM_005588.2) with metabolic disturbances in PCOS and healthy control women. Genetic variants rs17468190 (G/T) of MEP1A gene were analyzed in 576 PCOS women and 206 controls by using the Taqman fluorogenic 5'-exonuclease assay. This polymorphism was tested for association with anthropometric, metabolic, hormonal, and functional parameters of PCOS. There was a borderline significant difference in genotype distribution between PCOS and control women (p=0.046). In overweight/obese PCOS patients, the variants rs17468190 (G/T) in the MEP1A gene are associated with glucose and insulin metabolism. In a dominant model, the GG genotype of the MEP1A gene was more strongly associated with insulin metabolism in overweight/obese PCOS women (body mass index, BMI>25 kg/m(2)), than in GT+TT genotypes. The MEP1A GG-carriers showed a significantly increased homeostatic model assessment - insulin resistance (HOMA-IR) (p=0.003), elevation of fasting insulin (p=0.004) and stimulated insulin (30 min, p<0.001; 60 min, p=0.009; 120 min, p=0.009) as well as triglyceride (p=0.032) levels. MEP1A is a possible target gene for disease modification in PCOS. It might contribute to the abnormalities of glucose metabolism and insulin sensitivity and serve as a diagnostic or therapeutic target gene for PCOS.

Huang R, Ma Y, Holm R, et al.
Sex hormone-binding globulin (SHBG) expression in ovarian carcinomas and its clinicopathological associations.
PLoS One. 2013; 8(12):e83238 [PubMed] Free Access to Full Article Related Publications
Sex hormone-binding globulin (SHBG) is known as a carrier protein. It is classically thought to be mainly synthesized in the liver and then secreted into the circulating system, where it binds to sex steroids with a high affinity and modulates the bio-availability of the hormones. Other organs known to produce SHBG include brain, uterus, testis, prostate, breast and ovary, and the local expressed SHBG may play an important role in tumor development. However, SHBG expression status and its clinicopathological significance in ovarian cancer cells are not reported yet. In our present study, we examined and found the variable SHBG expression in four ovarian cancer cell lines (OV-90, OVCAR-3, SKOV-3 and ES-2) by immunocytochemistry and Western blotting. We then extended our study to 248 ovarian carcinoma samples, which were collected at The Norwegian Radium Hospital, Oslo University Hospital with complete clinical information, and discovered that SHBG was variably expressed in these ovarian carcinomas. Higher level of SHBG expression was significantly associated with more aggressive histological subtype (p = 0.022), higher FIGO stage (p = 0.018) and higher histological grade (grade of differentiation, p = 0.020), although association between SHBG expression and OS/PFS was not observed. Our results demonstrate that ovarian cancer cells produce SHBG and higher SHBG expression in ovarian carcinoma is associated with unfavorable clinicopathological features.

Svartberg J, Schirmer H, Wilsgaard T, et al.
Single-nucleotide polymorphism, rs1799941 in the Sex Hormone-Binding Globulin (SHBG) gene, related to both serum testosterone and SHBG levels and the risk of myocardial infarction, type 2 diabetes, cancer and mortality in men: the Tromsø Study.
Andrology. 2014; 2(2):212-8 [PubMed] Related Publications
Low testosterone levels are associated with metabolic and cardiovascular disease risk factor, and have been shown to predict type 2 diabetes mellitus (T2DM), myocardial infarction (MI) and all-cause mortality. It is not known if these associations are causal or not. Recently, it has been shown that the serum testosterone levels are associated with single-nucleotide polymorphisms (SNPs), and we therefore studied the associations between one of these SNPs, rs1799941 on the Sex Hormone-Binding Globulin (SHBG) gene, and MI, T2DM, cancer and death. DNA was prepared from men who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints MI, T2DM, cancer or death and a randomly selected control group. For mortality, the observation time was set from 1994, and for the other endpoints from birth. The endpoint data were completed up to 2010-2013. Genetic analyses were successfully performed in 5309 men, of whom 1454 were registered with MI, 638 with T2DM, 1534 with cancer and in 2226 who had died. Men with the minor homozygote genotype had significantly higher levels of total testosterone (14.7%) and SHBG (24.7%) compared with men with the major homozygote genotype, whereas free testosterone levels did not differ significantly between the genotypes. The SNP rs1799941 was not significantly associated with MI, T2DM, cancer or mortality. Thus, our result does not support a causal relationship between total testosterone and SHBG and MI, T2DM, cancer or mortality, suggesting that low testosterone more likely is a marker of poor health.

Berstein LM, Iyevleva AG, Vasilyev D, et al.
Genetic polymorphisms potentially associated with response to metformin in postmenopausal diabetics suffering and not suffering with cancer.
Cell Cycle. 2013; 12(23):3681-8 [PubMed] Free Access to Full Article Related Publications
Metformin is a well-known antidiabetic medication, which, besides diabetes, may be involved into modulation of other age-related pathologies, including cancer. The study concerns 12 gene polymorphisms divided into 2 groups consisting of 6 genes each. The first group was composed from so-called "standard" (S) polymorphisms, for which the connection with metabolic response to metformin is already established. The second group included polymorphisms of genes encoding proteins possibly connected with diabetes mellitus type 2 (DM2), impaired glucose tolerance or cancer and entitled here as "associated" (A). A total of 156 postmenopausal women (average age 60.7 ± 0.7) were included, 37 of them healthy, 64 with type DM2 and concurrent treatment-naïve cancer (mostly breast, endometrial or colorectal cancer), 32 with DM2 without cancer, and 23 with treatment-naïve cancer and normal glucose tolerance. The leading metformin response S-marker in combined group of DM2 patients was the CC variant of OCT1-R61C polymorphism of organic cation transporter protein 1 gene. In cancer patients without DM2, this position belonged to AC and AA genotypes of OCT1_rs622342 polymorphism. Among the A-polymorphisms, GA variant of sex hormone-binding globulin gene SHBG_D356N was less frequently observed in DM2 patients with or without cancer. Besides, in diabetics, the same polymorphic variant of SHBG as well as GC genotype of oxidized lipoprotein receptor OLR1_G501C and GG genotype of locus rs11065987 near BRAP gene were carried rather often in combination with "metformin-positive" variant of OCT1_R61C. In addition, carriers of OCT1_R61C and OCT1_rs622342 polymorphisms with potentially positive reaction to metformin had higher insulin resistance score (HOMA-IR) values. Received data lead to the conclusion that postmenopausal diabetics, both with and without cancer, differ in genetic stigmata of potential response to metformin less than they differ from cancer patients without DM2. As genetic polymorphisms associated with metabolic and anticancer metformin (and, possibly, phenformin) effects may be different, this subject requires further investigation.

Fabian CJ, Kimler BF, Donnelly JE, et al.
Favorable modulation of benign breast tissue and serum risk biomarkers is associated with > 10 % weight loss in postmenopausal women.
Breast Cancer Res Treat. 2013; 142(1):119-32 [PubMed] Free Access to Full Article Related Publications
We conducted a phase II feasibility study of a 6-month behavioral weight loss intervention in postmenopausal overweight and obese women at increased risk for breast cancer and the effects of weight loss on anthropomorphic, blood, and benign breast tissue biomarkers. 67 women were screened by random peri-areolar fine-needle aspiration, 27 were registered and 24 participated in the interventional phase. The 24 biomarker evaluable women had a median baseline BMI of 34.2 kg/m(2) and lost a median of 11 % of their initial weight. Significant tissue biomarker modulation after the 6-month intervention was noted for Ki-67 (if restricted to the 15 women with any Ki-67 at baseline, p = 0.041), adiponectin to leptin ratio (p = 0.003); and cyclin B1 (p = 0.001), phosphorylated retinoblastoma (p = 0.005), and ribosomal S6 (p = 0.004) proteins. Favorable modulation for serum markers was observed for sex hormone-binding globulin (p < 0.001), bioavailable estradiol (p < 0.001), bioavailable testosterone (p = 0.033), insulin (p = 0.018), adiponectin (p = 0.001), leptin (p < 0.001), the adiponectin to leptin ratio (p < 0.001), C-reactive protein (p = 0.002), and hepatocyte growth factor (p = 0.011). When subdivided by <10 or >10 % weight loss, change in percent total body and android (visceral) fat, physical activity, and the majority of the serum and tissue biomarkers were significantly modulated only for women with >10 % weight loss from baseline. Some factors such as serum PAI-1 and breast tissue pS2 (estrogen-inducible gene) mRNA were not significantly modulated overall but were when considering only those with >10 % weight loss. In conclusion, a median weight loss of 11 % over 6 months resulted in favorable modulation of a number of anthropomorphic, breast tissue and serum risk and mechanistic markers. Weight loss of 10 % or more should likely be the goal for breast cancer risk reduction studies in obese women.

Folkerd E, Dowsett M
Sex hormones and breast cancer risk and prognosis.
Breast. 2013; 22 Suppl 2:S38-43 [PubMed] Related Publications
The study of large prospective collections of plasma samples from women prior to the development of breast cancer has firmly established certain sex steroids as being significantly associated with risk. The strongest associations have been found in postmenopausal women in whom the within person variability of most hormones is markedly reduced but some positive associations have also been seen in premenopausal women. Plasma estrogens show the strongest correlations with risk and these are strengthened by measurement or calculation of the proportion of estradiol that circulates free of sex hormone binding globulin (SHBG), consistent with this being the most active fraction. The relationships have been reported to potentially explain virtually all of the association of breast cancer with body mass index in postmenopausal women; this is likely to be due to non-ovarian estrogen synthesis being prominent in subcutaneous fat. These strong relationships have led to plasma and urine estrogen levels being used as intermediate end-points in the search for genes that affect breast cancer risk via their role in steroid disposition. Plasma androgen levels also show a relationship with breast cancer risk that is weakened but not eliminated by 'correction' for estrogen levels. This has been argued to be evidence of the local production of estrogens being important in the etiology of breast cancer. Given that plasma steroid levels do not correlate closely with mammographic density, which is strongly associated with risk, the opportunity exists to combine the two factors in assessing breast cancer risk but the low availability of suitable estrogen assays is a major impediment to this. In established breast cancer, plasma estrogens have been found to correlate with gene expression of estrogen dependent genes and the expression of these varies across the menstrual cycle of premenopausal women. There is infrequently a need for routine measurement of plasma estrogen levels but it has been important in the comparative pharmacology and dose-related effectiveness of aromatase inhibitors. Measurement may be needed to identify residual ovarian function in women who have amenorrhea subsequent to cytotoxic chemotherapy indicating their unsuitability for aromatase inhibitor treatment. Use of highly sensitive assays has also revealed that the association between BMI and plasma estrogen levels persists in patients on 3rd generation aromatase inhibitors and that measurable increments in plasma estrogen levels occur with some vaginal estrogen preparations that are of concern in relation to treatment efficacy.

Ma Y, Liang D, Liu J, et al.
SHBG is an important factor in stemness induction of cells by DHT in vitro and associated with poor clinical features of prostate carcinomas.
PLoS One. 2013; 8(7):e70558 [PubMed] Free Access to Full Article Related Publications
Androgen plays a vital role in prostate cancer development. However, it is not clear whether androgens influence stem-like properties of prostate cancer, a feature important for prostate cancer progression. In this study, we show that upon DHT treatment in vitro, prostate cancer cell lines LNCaP and PC-3 were revealed with higher clonogenic potential and higher expression levels of stemness related factors CD44, CD90, Oct3/4 and Nanog. Moreover, sex hormone binding globulin (SHBG) was also simultaneously upregulated in these cells. When the SHBG gene was blocked by SHBG siRNA knock-down, the induction of Oct3/4, Nanog, CD44 and CD90 by DHT was also correspondingly blocked in these cells. Immunohistochemical evaluation of clinical samples disclosed weakly positive, and areas negative for SHBG expression in the benign prostate tissues, while most of the prostate carcinomas were strongly positive for SHBG. In addition, higher levels of SHBG expression were significantly associated with higher Gleason score, more seminal vesicle invasions and lymph node metastases. Collectively, our results show a role of SHBG in upregulating stemness of prostate cancer cells upon DHT exposure in vitro, and SHBG expression in prostate cancer samples is significantly associated with poor clinicopathological features, indicating a role of SHBG in prostate cancer progression.

Clendenen T, Zeleniuch-Jacquotte A, Wirgin I, et al.
Genetic variants in hormone-related genes and risk of breast cancer.
PLoS One. 2013; 8(7):e69367 [PubMed] Free Access to Full Article Related Publications
Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.

Ramos RB, Wiltgen D, Spritzer PM
Polymorphisms of TCF7L2 gene in South Brazilian women with polycystic ovary syndrome: a cross-sectional study.
Eur J Endocrinol. 2013; 169(5):569-76 [PubMed] Related Publications
OBJECTIVE: To assess whether TCF7L2 single nucleotide polymorphisms rs7903146 C/T and rs11196236 C/T are associated with polycystic ovary syndrome (PCOS) in South Brazilian women.
DESIGN: Cross-sectional study.
METHODS: Two hundred PCOS patients and 102 non-hirsute, ovulatory controls were genotyped by real-time PCR. Haplotypes were constructed from the combination of both polymorphisms. Frequencies were inferred using the PHASE 2.1.1 software.
RESULTS AND CONCLUSIONS: The distribution of rs7903146 (PCOS, 54.4% CC; 28.5% CT; 17.1% TT; controls, 51.0% CC; 37.0% CT; 12.0% TT) and rs11196236 (PCOS, 4.3% CC; 33.5% CT; 62.2% TT; controls, 3.2% CC; 35.5% CT; 61.3% TT) was similar between the groups. rs7903146 and rs11196236 were not in linkage disequilibrium (|D'|=0.34; r(2)=0.07). PCOS participants were younger, with higher age-adjusted BMI, waist circumference, blood pressure, triglycerides, insulin, homeostasis model assessment index to estimate insulin resistance and total testosterone, and lower HDL-C and sex hormone binding globulin vs controls. In PCOS, no differences between genotypes and haplotypes were found for clinical and metabolic variables. However, for each T (rs7903146) and T (rs11196236) allele added to the haplotypes, a variation of 5.87 cm in waist (P trend=0.01), 10.7 mg/dl in total cholesterol (P trend=0.03), and 10.3 mg/dl in LDL-C (P trend=0.01) was recorded. TCF7L2 variants are probably not implicated in PCOS development in South Brazilian women.

Kim HA, Nam K, Lee M, Kim SW
Hypoxia/hepatoma dual specific suicide gene expression plasmid delivery using bio-reducible polymer for hepatocellular carcinoma therapy.
J Control Release. 2013; 171(1):1-10 [PubMed] Free Access to Full Article Related Publications
Gene therapy is suggested as a promising alternative strategy of hepatocellular carcinoma (HCC, also called hepatoma) therapy. To achieve a successful and safe gene therapy, tight regulation of gene expression is required to minimize side-effects in normal tissues. In this study, we developed a novel hypoxia and hepatoma dual specific gene expression vector. The constructed vectors were transfected into various cell lines using bio-reducible polymer, PAM-ABP. First, pAFPS-Luc or pAFPL-Luc vector was constructed with the alpha-fectoprotein (AFP) promoter and enhancer for hepatoma tissue specific gene expression. Then, pEpo-AFPL-Luc was constructed by insertion of the erythropoietin (Epo) enhancer for hypoxic cancer specific gene expression. In vitro transfection assay showed that pEpo-AFPL-Luc transfected hepatoma cell increased gene expression under hypoxic condition. To confirm the therapeutic effect of dual specific vector, herpes simplex virus thymidine kinase (HSV-TK) gene was introduced for cancer cell killing. The pEpo-AFPL-TK was transfected into hepatoma cell lines in the presence of ganciclovir (GCV) pro-drug. Caspase-3/7, MTT and TUNEL assays elucidated that pEpo-AFPL-TK transfected cells showed significant increasing of death rate in hypoxic hepatoma cells compared to controls. Therefore, the hypoxia/hepatoma dual specific gene expression vector with the Epo enhancer and AFP promoter may be useful for hepatoma specific gene therapy.

Serrano D, Lazzeroni M, Gandini S, et al.
A randomized phase II presurgical trial of weekly low-dose tamoxifen versus raloxifene versus placebo in premenopausal women with estrogen receptor-positive breast cancer.
Breast Cancer Res. 2013; 15(3):R47 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: We previously demonstrated that 1 or 5 mg per day of tamoxifen (T) given for four weeks before surgery reduces Ki-67 in breast cancer (BC) patients to the same extent as the standard 20 mg/d. Given the long half-life of T, a weekly dose (10 mg per week (w)) may be worth testing. Also, raloxifene (R) has shown Ki-67 reduction in postmenopausal patients in a preoperative setting, but data in premenopausal women are limited. We conducted a randomized trial testing T 10 mg/w vs. R 60 mg/d vs. placebo in a presurgical model.
METHODS: Out of 204 screened subjects, 57 were not eligible, 22 refused to participate and 125 were included in the study. The participants were all premenopausal women with estrogen receptor-positive BC. They were randomly assigned to either T 10mg/w or R 60 mg/d or placebo for six weeks before surgery. The primary endpoint was tissue change of Ki-67. Secondary endpoints were modulation of estrogen and progesterone receptors and several other circulating biomarkers.
RESULTS: Ki-67 was not significantly modulated by either treatment. In contrast, both selective estrogen receptor modulators (SERMs) significantly modulated circulating IGF-I/IGFBP-3 ratio, cholesterol, fibrinogen and antithrombin III. Estradiol was increased with both SERMs. Within the tamoxifen arm, CYP2D6 polymorphism analysis showed a higher concentration of N-desTamoxifen, one of the tamoxifen metabolites, in subjects with reduced CYP2D6 activity. Moreover, a reduction of Ki-67 and a marked increase of sex hormone-binding globulin (SHBG) were observed in the active phenotype.
CONCLUSIONS: A weekly dose of tamoxifen and a standard dose of raloxifene did not inhibit tumor cell proliferation, measured as Ki-67 expression, in premenopausal BC patients. However, in the tamoxifen arm women with an extensive phenotype for CYP2D6 reached a significant Ki-67 modulation.

Fan W, Li S, Chen Q, Huang Z
Association between the (TAAAA)n SHBG polymorphism and PCOS: a systematic review and meta-analysis.
Gynecol Endocrinol. 2013; 29(7):645-50 [PubMed] Related Publications
Human sex hormone-binding globulin (SHBG) is a specific plasma transport glycoprotein for sex steroid hormones, and serum SHBG levels were decreased in polycystic ovary syndrome (PCOS) patients. To clarify the conflicting data in the literature concerning the association between PCOS and the (TAAAA)n SHBG polymorphism, and influence of the (TAAAA)n SHBG polymorphism on serum SHBG levels of PCOS patients, a systematic review and meta-analysis was performed in this study. Literature search was conducted through PubMed, EMBASE and China National Knowledge Infrastructure. Five studies were included, representing 1595 individuals. No statistically significant associations were found between the (TAAAA)n SHBG allele and genotype with PCOS risk. Moreover, because the influence of the (TAAAA)n SHBG polymorphism on serum SHBG levels of PCOS patients in studies included in our review was investigated in different way to classify the alleles, we were unable to perform a meta-analysis and hence could not draw any conclusions. In conclusion, this study indicates that there is insufficient evidence to demonstrate a conclusive association between the (TAAAA)n SHBG polymorphism with the risk of PCOS, which needs to be further confirmed by further studies.

Skrgatić L, Baldani DP, Gersak K, et al.
Genetic polymorphisms of INS, INSR and IRS-1 genes are not associated with polycystic ovary syndrome in Croatian women.
Coll Antropol. 2013; 37(1):141-6 [PubMed] Related Publications
Obesity and insulin resistance is a common finding in patients with polycystic ovary syndrome (PCOS). Significant number of PCOS women experience insulin resistance that is irrespective of the degree of obesity suggesting possible genetic basis. Therefore, several polymorphisms of the genes encoding for the insulin (INS), insulin receptor (INSR) or insulin receptor substrates (IRS) involved in postreceptor signaling have been explored for their association with abnormal sensitivity to insulin in PCOS. The aim of the present study was to determine whether selected polymorphisms of INS, INSR and IRS-1 are associated with the development of PCOS as well as with increased insulin resistance in Croatian women with PCOS. The study enrolled 150 women with PCOS and 175 control women. The diagnosis of PCOS was based on Rotterdam consensus criteria. Each subject underwent an evaluation of body mass index (BMI), hirsutism, acne and menstrual cycle abnormalities as well as follicular stimulating hormone (FSH), luteinizing hormone (LH), total and free testosterone, androstendione, dehydroepiandrosterone sulphate (DHEAS), sex hormone binding globulin (SHBG), fasting glucose and fasting insulin. Insulin resistance (IR) was quantified using the homeostatic model assessment of IR (HOMA-IR). Molecular analyses for the genetic polymorphisms were preformed. There was a significant difference in clinical and biochemical characteristics of the studied groups except for BMI and fasting glucose levels. No significant differences were observed in the genotype and allele distribution of the VNTR INS, C/T INSR, Gly792Arg IRS-1 polymorphisms between cases and controls. Moreover, no association was found between VNTR INS, C/T INSR and Gly792Arg IRS-1 polymorphism and parameters of insulin resistance in PCOS patients. In conclusion, our data does not support an association between VNTR INS, C/T INSR and Gly792Arg IRS-1 polymorphism and susceptibility to PCOS or insulin resistance in Croatian women with PCOS.

Carvajal R, Rosas C, Kohan K, et al.
Metformin augments the levels of molecules that regulate the expression of the insulin-dependent glucose transporter GLUT4 in the endometria of hyperinsulinemic PCOS patients.
Hum Reprod. 2013; 28(8):2235-44 [PubMed] Related Publications
STUDY QUESTION: Does treatment with the insulin sensitizer metformin modify the levels and activation of proteins related to the expression of the insulin-dependent glucose transporter (GLUT4), such as adenosine monophosphate-activated protein kinase (AMPK) and myocyte enhancer factor 2A (MEF2A), in endometria from hyperinsulinemic hyperandrogenemic polycystic ovary syndrome (PCOS h-Ins) patients?
SUMMARY ANSWER: In PCOS h-Ins patients, metformin increases endometrial levels of GLUT4 mRNA and protein levels by normalizing the quantity and activation of molecules that regulate GLUT4 expression to healthy values. These changes could improve endometrial metabolic function.
WHAT IS ALREADY KNOWN: PCOS is an endocrine-metabolic disorders closely associated with insulin resistance. In particular, the insulin signaling pathway is impaired in endometria from these patients and the concentration of GLUT4, as well as the molecules involved in its translocation to the cell surface, is decreased. However, there are limited data about the mechanisms that regulate the GLUT4 expression in the endometria and the effect of metformin on them.
STUDY DESIGN, SIZE AND DURATION: This is a case-control study in the setting of a research unit, approved by the Ethical Committees of our institution. The groups whose endometria were studied were PCOS h-Ins (n = 8); PCOS patients with hyperandrogenemia hyperinsulinemia taking only metformin for at least 3 months (PCOS-MTF, n = 8) and healthy fertile women at the time of hysterectomy because of benign pathology as controls (CE, n = 8).
PARTICIPANTS/MATERIALS, SETTING, METHODS: Steroids and sex hormone-binding globulin were measured and glucose and insulin levels were evaluated during an oral glucose tolerance test. Protein levels for αAMPK (catalytic subunit of AMPK), phosphorylated (p)-AMPKαThr(172) (activating phosphorylation site), MEF2A, p-MEF2AThr312 (activating phosphorylation site) and GLUT4 were assessed by western blot and immunohistochemistry. In addition, GLUT4 gene expression was evaluated by RT-PCR.
MAIN RESULTS AND THE ROLE OF CHANCE: We found significantly lower levels of MEF2A and p-MEF2AThr312 in PCOS h-Ins compared with CE endometria (P < 0.05). Also, we detected lower levels of p-AMPKαThr(172) in PCOS h-Ins endometria compared with the PCOS-MTF group (P < 0.05). The ratios of phospho-AMPK/total AMPK and phospho-MEF2A/total MEF2A were significantly increased in the PCOS-MTF compared with the PCOS h-Ins group (P < 0.05). The RT-PCR experiments showed lower levels of GLUT4 mRNA transcripts in PCOS h-Ins compared with PCOS-MTF-treated group (P < 0.05), the protein levels of GLUT4 were decreased in a similar way.
LIMITATIONS, REASONS FOR CAUTION: The limited number of patients included in this study who presented large clinical variability. Therefore, it would be necessary to recruit a greater number of patients to minimize our data dispersion in order to prove the clinical benefits of metformin described by others.
WIDER IMPLICATIONS OF THE FINDINGS: Since the insulin sensitizer metformin increases the expression of the GLUT4, it may improve endometrial physiology in PCOS patients and, therefore, promote better reproductive outcomes. These results suggest that in PCOS patients, metformin may act directly at the endometrial level and decrease insulin resistance condition by increasing the expression of GLUT4 and, in this way, indirectly restore endometrial function.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (grant number 1095127 to M.V.). None of the authors has any conflict of interest to declare.

Florinas S, Nam HY, Kim SW
Enhanced siRNA delivery using a combination of an arginine-grafted bioreducible polymer, ultrasound, and microbubbles in cancer cells.
Mol Pharm. 2013; 10(5):2021-30 [PubMed] Free Access to Full Article Related Publications
RNAi-based gene therapy for cancer treatment has not shown significant clinical impact due to poor siRNA delivery to the target site. Here, we design a nonviral siRNA gene carrier using a combination of an arginine-grafted bioreducible polymer (ABP), microbubbles (MB), and ultrasound (US), for targeting vascular endothelial growth factor (VEGF) in a human ovarian cancer cell line. Newly designed MBs with a perfluorocrownether gas core show higher stability compared to controls. Further, MBs in combination with polyplexes show a significant higher loading capacity compared to naked siRNA. Lastly, only siRNA-ABP-MB (SAM) complexes in combination with US show significant VEGF knock down in A2780 human ovarian cancer cell line compared to naked siRNA when incubated for a short time after sonication treatment.

Monteiro C, Sousa MV, Ribeiro R, et al.
Genetic variants in AR and SHBG and resistance to hormonal castration in prostate cancer.
Med Oncol. 2013; 30(1):490 [PubMed] Related Publications
Castration resistance is a life-threatening event that may develop in prostate cancer patients with advanced disease following hormonal castration therapy (HCT). Current understanding of the molecular mechanisms behind resistance to hormonal castration suggests a role for androgen receptor signaling and bioavailability of androgens. We evaluated whether common functional polymorphisms in AR and SHBG genes associate with response to HCT. The study included 203 prostate cancer patients with advanced disease treated with hormonal castration. Genomic DNA was isolated from whole blood, and the genetic polymorphisms AR +1733 G>A and SHBG +5790 G>A were determined by real-time PCR. Genetic variants were associated with response to treatment and time to resistance to hormonal castration. Multivariate analysis showed increased risk of developing resistance to hormonal castration in homozygous GG carriers of the SHBG +5790 G>A (HR = 1.9, 95 % CI 1.1-3.3, P = 0.019) polymorphism alone and when functionally combined with AR +1733 G>A into a high AR pathway activation genetic profile (HR = 1.9, 95 % CI 1.1-3.1, P = 0.015), after adjustment for age, PSA, Gleason's score and clinical stage. Our results suggest that the SHBG +5790 G>A polymorphism may be a useful marker to include in the pharmacogenomic profile of prostate cancer resistant to hormonal castration.

Pau C, Saxena R, Welt CK
Evaluating reported candidate gene associations with polycystic ovary syndrome.
Fertil Steril. 2013; 99(6):1774-8 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To replicate variants in candidate genes associated with polycystic ovary syndrome (PCOS) in a population of European women with PCOS and control subjects.
DESIGN: Case-control association analysis and meta-analysis.
SETTING: Major academic hospital.
PATIENT(S): Women of European ancestry with PCOS (n = 525) and controls (n = 472), aged 18-45 years.
INTERVENTION(S): Variants previously associated with PCOS in candidate gene studies were genotyped (n = 39). Metabolic, reproductive, and anthropomorphic parameters were examined as a function of the candidate variants. All genetic association analyses were adjusted for age, body mass index, and ancestry and were reported after correction for multiple testing.
MAIN OUTCOME MEASURE(S): Association of candidate gene variants with PCOS.
RESULT(S): Three variants, rs3797179 (SRD5A1), rs12473543 (POMC), and rs1501299 (ADIPOQ), were nominally associated with PCOS. However, they did not remain significant after correction for multiple testing, and none of the variants replicated in a sufficiently powered meta-analysis. Variants in the FBN3 gene (rs17202517 and rs73503752) were associated with smaller waist circumferences, and variant rs727428 in the SHBG gene was associated with lower sex hormone-binding globulin levels.
CONCLUSION(S): Previously identified variants in candidate genes do not seem to be associated with PCOS risk.
CLINICAL TRIAL REGISTRATION NUMBER: NCT00166569.

Hyland PL, Freedman ND, Hu N, et al.
Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma.
Carcinogenesis. 2013; 34(5):1062-8 [PubMed] Free Access to Full Article Related Publications
In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.

Hacıhanefioğlu B, Aybey B, Hakan Özön Y, et al.
Association of anthropometric, androgenic and insulin-related features with polymorphisms in exon 8 of SHBG gene in women with polycystic ovary syndrome.
Gynecol Endocrinol. 2013; 29(4):361-4 [PubMed] Related Publications
OBJECTIVE: Sex hormone binding globulin (SHBG) levels are often low in women with polycystic ovary syndrome (PCOS). In addition to metabolic and nutritional factors, SHBG levels are determined by genetic polymorphisms in SHBG gene. The aim of this study was to investigate the association of polymorphisms in exon 8 of SHBG gene with anthropometric and biochemical features of women with PCOS.
DESIGN: Prospective, observational study.
PATIENTS: One hundred and ninety-four women with PCOS.
MAIN OUTCOME MEASURE(S): Genotype analysis of exon 8 in SHBG gene was performed. Serum SHBG, total testosterone, free testosterone, 17-α-hydroxyprogesterone, TSH, PRL, glucose and insulin levels were determined. MAIN FINDING(S): Single nucleotide polymorphism (SNP) E326K located at codon 326 in exon 8 of SHBG gene was identified. Serum SHBG levels decreased significantly with increasing copy number of the variant allele for SNP E326K after adjustment for BMI, androgenic and insulin-related traits. Genotype analysis also revealed SNP, rs6259, located at codon 327 in exon 8 of SHBG gene, which is not associated with SHBG levels.
CONCLUSION: SNP, E326K, in exon 8 of SHBG gene may influence the metabolism of SHBG independently of BMI, androgenic and insulin-related features in women with PCOS.

Kosova G, Urbanek M
Genetics of the polycystic ovary syndrome.
Mol Cell Endocrinol. 2013; 373(1-2):29-38 [PubMed] Free Access to Full Article Related Publications
Polycystic ovary syndrome (PCOS) is a highly complex endocrine disorder, characterized by hyperandrogenemia, menstrual irregularities and polycystic ovaries. A strong genetic component to the etiology of PCOS is evident. However, due to the genetic and phenotypic heterogeneity of PCOS and the lack of insufficiently large cohorts, studies to identify specific contributing genes to date have yielded only few conclusive results. In this review we discuss the current status of the genetic analysis of PCOS including the results of numerous association studies with candidate genes involved in TGF-β and insulin signaling, type 2 diabetes mellitus and obesity susceptibility. Furthermore, we address current challenges in genetic studies of PCOS, and the promise of new approaches, including genome-wide association studies and next-generation sequencing.

Martínez-García MÁ, Gambineri A, Alpañés M, et al.
Common variants in the sex hormone-binding globulin gene (SHBG) and polycystic ovary syndrome (PCOS) in Mediterranean women.
Hum Reprod. 2012; 27(12):3569-76 [PubMed] Related Publications
STUDY QUESTION: Is there an association between polycystic ovary syndrome (PCOS) and the sex hormone-binding globulin (SHBG) rs1799941, rs6257, rs6259 and rs727428 variants in a large series of Mediterranean women?
SUMMARY ANSWER: The rs727428 and rs6259 variants are associated with PCOS in Mediterranean women.
WHAT IS KNOWN ALREADY: The level of SHBG, the primary plasma transport protein for sex steroids, which regulates the bioavailability of these hormones to target tissues, is reduced in patients with PCOS. Single-nucleotide polymorphisms in the SHBG gene influence circulating SHBG levels in American patients with PCOS and may predict the development of type 2 diabetes.
STUDY DESIGN, SIZE AND DURATION: This was a genetic case-control association study including 1004 premenopausal Mediterranean women.
PARTICIPANTS/MATERIALS, SETTING AND METHODS: In an Academic setting, we genotyped a clinical cohort consisting of 281 patients with PCOS and 142 women without any evidence of androgen excess, and a population-based cohort comprised of 581 unselected female blood donors from Spain and Italy. The latter included 31 patients with PCOS and 550 controls, of whom 298 had no evidence of any androgen excess disorder and were considered hyper-normal controls.
MAIN RESULTS AND THE ROLE OF CHANCE: Mutant alleles of the rs727428 variant were more frequent in patients with PCOS compared with controls and with hyper-normal controls. This association was independent of obesity. Carrying mutant alleles of rs727428 was found to be associated with a 1.29 odds ratio (OR) for PCOS, whereas carrying mutant alleles of rs6259 associated with a 0.68 OR for PCOS. The rs1799941 and rs6257 variants were not associated with PCOS. None of the SHBG variants influenced serum SHBG concentrations.
LIMITATIONS AND REASONS FOR CAUTION: The associations found here were relatively weak and, arising from a case-control study, do not necessarily indicate a causative role of the SHBG variants in the development of PCOS. Also, we studied different patients and controls from different sources, making some of the interpretations difficult. Finally, the rs1799941 variant was not in Hardy-Weinberg equilibrium in the small group of patients with PCOS recruited from the general population, yet this variant was not associated with PCOS.
WIDER IMPLICATIONS OF THE FINDINGS: SHBG variants that influenced circulating SHBG levels in American patients with PCOS are also associated with this syndrome in Mediterranean women, pointing to SHBG as a candidate gene for PCOS.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants PI080944 and PI110357 from Instituto de Investigación Carlos III, Spanish Ministry of Economy and Competitiveness. CIBERDEM is also an initiative of Instituto de Investigación Carlos III. The Authors have no competing interests to declare.

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