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NF-κB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance.
Austin DC, Strand DW, Love HL, Franco OE, Grabowska MM, Miller NL, Hameed O, Clark PE, Matusik RJ, Jin RJ, Hayward SW
(2016) Prostate 76: 1004-18
MeSH Terms: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, 5-alpha Reductase Inhibitors, Animals, Apoptosis, Drug Resistance, Gene Expression, Gene Knockdown Techniques, Humans, Isoenzymes, Lower Urinary Tract Symptoms, Male, Membrane Proteins, Mice, Mice, Nude, NF-kappa B, Orchiectomy, Prostate, Prostatic Hyperplasia, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Testosterone, Treatment Failure, Up-Regulation
Show Abstract · Added April 18, 2017
BACKGROUND - Benign prostatic hyperplasia (BPH) is treated with 5α-reductase inhibitors (5ARI). These drugs inhibit the conversion of testosterone to dihydrotestosterone resulting in apoptosis and prostate shrinkage. Most patients initially respond to 5ARIs; however, failure is common especially in inflamed prostates, and often results in surgery. This communication examines a link between activation of NF-κB and increased expression of SRD5A2 as a potential mechanism by which patients fail 5ARI therapy.
METHODS - Tissue was collected from "Surgical" patients, treated specifically for lower urinary tract symptoms secondary to advanced BPH; and, cancer free transition zone from "Incidental" patients treated for low grade, localized peripheral zone prostate cancer. Clinical, molecular and histopathological profiles were analyzed. Human prostatic stromal and epithelial cell lines were genetically modified to regulate NF-κB activity, androgen receptor (AR) full length (AR-FL), and AR variant 7 (AR-V7) expression.
RESULTS - SRD5A2 is upregulated in advanced BPH. SRD5A2 was significantly associated with prostate volume determined by Transrectal Ultrasound (TRUS), and with more severe lower urinary tract symptoms (LUTS) determined by American Urological Association Symptom Score (AUASS). Synthesis of androgens was seen in cells in which NF-κB was activated. AR-FL and AR-V7 expression increased SRD5A2 expression while forced activation of NF-κB increased all three SRD5A isoforms. Knockdown of SRD5A2 in the epithelial cells resulted in significant reduction in proliferation, AR target gene expression, and response to testosterone (T). In tissue recombinants, canonical NF-κB activation in prostatic epithelium elevated all three SRD5A isoforms and resulted in in vivo growth under castrated conditions.
CONCLUSION - Increased BPH severity in patients correlates with SRD5A2 expression. We demonstrate that NF-κB and AR-V7 upregulate SRD5A expression providing a mechanism to explain failure of 5ARI therapy in BPH patients. Prostate 76:1004-1018, 2016. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
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23 MeSH Terms
Evaluating use patterns of and adherence to medications for benign prostatic hyperplasia.
Nichol MB, Knight TK, Wu J, Barron R, Penson DF
(2009) J Urol 181: 2214-21; discussion 2221-2
MeSH Terms: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, 5-alpha Reductase Inhibitors, Adult, Age Factors, Aged, Cohort Studies, Dose-Response Relationship, Drug, Drug Administration Schedule, Finasteride, Follow-Up Studies, Humans, Logistic Models, Male, Middle Aged, Multivariate Analysis, Patient Compliance, Patient Dropouts, Probability, Proportional Hazards Models, Prostatic Hyperplasia, Registries, Retrospective Studies, Risk Assessment, Severity of Illness Index
Show Abstract · Added March 5, 2014
PURPOSE - We investigated adherence to benign prostatic hyperplasia medications in a California Medicaid population.
MATERIALS AND METHODS - Using California Medicaid data on 1995 to 2004 we identified adult males 40 years old or older with 1 or more diagnosis and 2 or more prescription fills for benign prostatic hyperplasia. Patients with 2 fills on the same day were assigned to the multiple medication cohort. Adherence was measured using the medication possession ratio for the index medication and the proportion of days covered for any benign prostatic hyperplasia medication. Patients with a medication possession ratio or proportion of days covered of 0.8 or greater were considered adherent. A Cox proportional hazards model was used to assess the relative hazards associated with discontinuation. Multiple logistic regression was used to investigate factors associated with nonadherence or a benign prostatic hyperplasia related procedure.
RESULTS - Of the total population of 2,640 men 40% were adherent with any benign prostatic hyperplasia medication. A significantly greater proportion of patients using multiple medications and finasteride were adherent with any benign prostatic hyperplasia medication (62% and 55%, respectively, p <0.0001). Doxazosin, terazosin and tamsulosin use was associated with nonadherence (p = 0.008, 0.04 and 0.03, respectively). Younger patients and those changing medications were more likely to discontinue (p = 0.01 and <0.0001), while patients using multiple medications and those experiencing a gap were at lower risk for discontinuation (p = 0.01 and <0.0001, respectively). Predictors of a procedure included an index prescription in 1999 or later, a urologist visit and nonadherence to any benign prostatic hyperplasia medication (p = 0.01, <0.0001 and <0.0001, respectively).
CONCLUSIONS - Adherence to alpha-blockers was less than adherence to finasteride or multiple medications and nonadherence was significantly associated with a procedure. Interventions focused on improving adherence to benign prostatic hyperplasia medications are clearly needed.
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24 MeSH Terms
Steroid hormones and hormone-related genetic and lifestyle characteristics as risk factors for benign prostatic hyperplasia: review of epidemiologic literature.
Neuhouser ML, Kristal AR, Penson DF
(2004) Urology 64: 201-11
MeSH Terms: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Aged, Alcohol Drinking, Case-Control Studies, Cohort Studies, Comorbidity, Cross-Sectional Studies, Diet, Genetic Predisposition to Disease, Gonadal Steroid Hormones, Humans, Life Style, Male, Middle Aged, Motor Activity, Obesity, Prostatic Hyperplasia, Receptors, Androgen, Receptors, Calcitriol, Risk Factors, Smoking, Steroid 17-alpha-Hydroxylase, Trinucleotide Repeats, United States
Added March 5, 2014
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24 MeSH Terms
A case-based evaluation of SRD5A1, SRD5A2, AR, and ADRA1A as candidate genes for severity of BPH.
Klotsman M, Weinberg CR, Davis K, Binnie CG, Hartmann KE
(2004) Pharmacogenomics J 4: 251-9
MeSH Terms: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Aged, Codon, Humans, Male, Muscle Tonus, Muscle, Smooth, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Prostate, Prostatic Hyperplasia, Receptors, Androgen, Trinucleotide Repeats
Show Abstract · Added March 5, 2014
In men with a clinical diagnosis of benign prostatic hyperplasia (BPH), polytomous logistic regression analysis was conducted to evaluate associations between two silent polymorphisms in SRD5A1 (codon positions 30 and 116), two polymorphisms in SRD5A2 (Val89Leu substitution and C to T transition in intron 1), a trinucleotide (CAG)n repeat in androgen receptor (AR), and an Arg492Cys substitution in ADRA1A and clinical parameters that characterize severity of BPH. Candidate gene selection was based on two mechanistic pathways targeted by pharmacotherapy for BPH: (1) androgen metabolic loci contributing to prostate growth (static obstruction); and (2) factors affecting smooth muscle tone (dynamic obstruction). Polymorphisms in SRD5A2 were not associated with severity of BPH; however, SRD5A1 polymorphisms were associated with severity of BPH. The process(es) in which these silent single-nucleotide polymorphisms (SNPs) influence BPH phenotypes is unknown and additional studies will be needed to assess whether these SNPs have direct functional consequences. The characterization of additional molecular factors that contribute to static and dynamic obstruction may help predict response to pharmacotherapy and serve to identify novel drug targets for the clinical management of BPH.
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13 MeSH Terms