Kristin Austlid Taskén

Association between use of β-blockers and prostate cancer-specific survival: A cohort study of 3561 prostate cancer patients with high-risk or metastatic disease

BACKGROUND We recently reported reduced prostate cancer (PCa)-specific mortality for β-blocker users among patients receiving androgen-deprivation therapy in a health survey cohort including 655 PCa patients. Information on clinical characteristics was limited. OBJECTIVE To assess the association between β-blockers and PCa-specific mortality in a cohort of 3561 prostate cancer patients with high-risk or metastatic disease, and to address potential confounding from the use of statins or acetylsalicylic acid (ASA). DESIGN, SETTING, AND PARTICIPANTS Clinical information from all men reported to the Cancer Registry of Norway with a PCa diagnosis between 2004 and 2009 (n=24 571) was coupled with information on filled prescriptions between 2004 and 2011 from the Norwegian Prescription Database. Exclusion criteria were low- or intermediate-risk disease; planned radiotherapy or radical prostatectomy; initiation of β-blocker, ASA, or statin use after diagnosis where applicable; missing information on baseline Gleason score, prostate-specific antigen level, T stage or performance status; and missing follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox proportional hazards modelling and competing risk regression modelling were used to analyse the effects of β-blocker use on all-cause and PCa-specific mortality, respectively. Differences between β-blocker users and nonusers regarding baseline clinical characteristics were assessed by the Wilcoxon-Mann-Whitney U test, Pearson chi-square test, and Student t test. RESULTS AND LIMITATIONS Median follow-up was 39 mo. β-Blocker use was associated with reduced PCa mortality (adjusted subhazard ratio: 0.79; 95% confidence interval [CI], 0.68-0.91; p value: 0.001). The observed reduction in PCa mortality was independent of the use of statins or ASA. We observed no association with all-cause mortality (adjusted hazard ratio: 0.92; 95% CI, 0.83-1.02). The main limitations of the study were the observational study design and short follow-up. CONCLUSIONS β-Blocker use was associated with reduced PCa-specific mortality in patients with high-risk or metastatic disease at the time of diagnosis. Our findings need validation from further observational studies.

Use of β-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy.

Experimental evidence suggests a role for the β2‐adrenergic receptor pathway in prostate cancer (PCa). We have investigated the association of β‐blocker use with PCa incidence and survival in a Norwegian cohort.

Efficacy and safety of short-term genistein intervention in patients with localized prostate cancer prior to radical prostatectomy: a randomized, placebo-controlled, double-blind Phase 2 clinical trial.

We conducted a placebo-controlled, block-randomized double-blind Phase 2 study to examine the effect of 30 mg synthetic genistein daily on serum and tissue biomarkers in patients with localized prostate cancer (CaP). Fifty-four study subjects were recruited and randomized to treatment with genistein (n = 23) or placebo (n = 24) for 3 to 6 wk prior to prostatectomy. Seven study subjects were noncompliant to the study protocol. Adverse events were few and mild. Serum prostate specific antigen (PSA) decreased by 7.8% in the genistein arm and increased by 4.4% in the placebo arm (P = 0.051). The PSA level was reduced in tumor tissue compared to normal tissue in the placebo arm. In the genistein arm, the PSA level in tumor and normal tissue was comparable. Total cholesterol was significantly lower in the genistein arm (P = 0.013). There were no significant effects on thyroid or sex hormones. Plasma concentrations of total genistein were on average 100-fold higher in the genistein arm after treatment (P < 0.001). Genistein at a dose that can be easily obtained from a diet rich in soy reduced the level of serum PSA in patients with localized CaP, without any effects on hormones. It was well tolerated and had a beneficial effect on blood cholesterol.

Distinct but overlapping domains of AKAP95 are implicated in chromosome condensation and condensin targeting

A‐kinase (or PKA)‐anchoring protein AKAP95 is a zinc‐finger protein implicated in mitotic chromosome condensation by acting as a targeting molecule for the condensin complex. We have identified determinants of chromatin‐binding, condensin‐targeting and chromosome‐condensation activities of AKAP95. Binding of AKAP95 to chromatin is conferred by residues 387–450 and requires zinc finger ZF1. Residues 525–569 are essential for condensation of AKAP95‐free chromatin and condensin recruitment to chromosomes. Mutation of either zinc finger of AKAP95 abolishes condensation. However, ZF1 is dispensable for condensin targeting, whereas the C‐terminal ZF2 is required. AKAP95 interacts with Xenopus XCAP‐H condensin subunit in vitro and in vivo but not with the human hCAP‐D2 subunit. The data illustrate the involvement of overlapping, but distinct, domains of AKAP95 for condensin recruitment and chromosome condensation and argue for a key role of ZF1 in chromosome condensation and ZF2 in condensin targeting. Moreover, condensin recruitment to chromatin is not sufficient to promote condensation.

Isoform-Specific Regulation of the CCAAT/Enhancer-Binding Protein Family of Transcription Factors by 3′,5′-Cyclic Adenosine Monophosphate in Sertoli Cells

The C/EBP (CCAAT/enhancer-binding protein) family of transcription factors is important for differentiation, lipid biosynthesis, and metabolism. Here, we demonstrate for the first time the presence of C/EBP α, β, δ, and ζ messenger RNA (mRNA) and protein in Sertoli cell primary cultures. Treatment with FSH or 8-CPTcAMP strongly induced C/EBP β mRNA above basal levels with rapid and transient kinetics in Sertoli cell primary cultures as well as in whole testes from hypophysectomized rats. Whereas C/EBP β mRNA was induced approximately 50-fold, C/EBP δ mRNA was induced 5- to 8-fold by cAMP in Sertoli cells. Messenger RNA for C/EBP β and δ were induced by inhibition of protein synthesis with cycloheximide and cycloheximide acted synergistically with cAMP. Immunoblots with C/EBP antibodies demonstrated a strong induction of C/EBP β, δ, and ζ by cAMP. Electrophoretic mobility shift analysis of nuclear proteins from cAMP-treated Sertoli cells using a C/EBP consensus oligonucleotide and antibodies revealed speci...

Regulation of PBX3 expression by androgen and Let-7d in prostate cancer.

BackgroundThe pre-leukemia transcription factor 3 (PBX) is part of the PBX family of transcription factors, which is known to regulate genes involved in differentiation of urogenital organs and steroidogenesis. This is of interest with regard to prostate cancer progression as regulation of steroidogenesis is one of the mechanisms involved in the development of castration-resistant prostate cancer. In light of this we wanted to investigate the possible involvement of androgen regulation of PBX3 expression in prostate cancer.ResultsIn this study, we show that PBX3 is post-transcriptionally regulated by androgen in prostate cancer cells and that the effect might be independent of the androgen receptor. Furthermore, PBX3 was identified as a target of Let-7d, an androgen regulated microRNA. Let-7d was down-regulated in malignant compared to benign prostate tissue, whereas up-regulation of PBX3 expression was observed.ConclusionsWe demonstrate that PBX3 is up-regulated in prostate cancer and post- transcriptionally regulated by androgen through Let-7d.

Regulation of Tissue Inhibitor of Metalloproteinases-1 in Rat Sertoli Cells: Induction by Germ Cell Residual Bodies, Interleukin-1α, and Second Messengers

Abstract In the testis, FSH has been shown to induce the expression and secretion of tissue inhibitor of metalloproteinases-1 (TIMP-1) from Sertoli cells in vitro. This study was performed to elucidate further the cellular origin of testicular TIMP-1 and its expression by hormonal and paracrine factors. This is the first report on the expression of testicular TIMP-1 in vivo. TIMP-1 mRNA in whole testis was decreased after hypophysectomy and strongly increased by the injection of FSH-S17 to hypophysectomized rats. Primary cultures of both peritubular and Sertoli cells showed basal expression of TIMP-1 mRNA. In contrast, we were unable to detect TIMP-1 mRNA in Leydig cells, freshly isolated immature germ cells (primary spermatocytes and spermatids), or residual bodies. We further show that treatment of Sertoli cells with 8-(4-chlorophenyl)thio-cAMP (8-CPTcAMP) in combination with 12-O-tetradecanoylphorbol 13-acetate (TPA) or Ca2+ inducers (calcium ionophore A23187 or thapsigargin) had additive (TPA) and synergistic effects (Ca2+) on the level of TIMP-1 mRNA and secreted protein. We also show that both the level of TIMP-1 mRNA and secreted protein from Sertoli cells were strongly increased by residual bodies, as well as by the cytokine interleukin-1α. TIMP-1 was not up-regulated by either 8-CPTcAMP or interleukin-1α in peritubular cells. In contrast to the regulated secretory fraction of TIMP-1, we also detected constitutively expressed immunoreactive TIMP-1 in the nucleus of Sertoli cells, suggesting a role of nuclear TIMP-1 in these cells. In conclusion, our data show that secretion of TIMP-1 from Sertoli cells is highly regulated by hormonal and local processes in the testis, indicating that TIMP-1 is of physiological importance during both testicular development and spermatogenesis.

Hormonal regulation of beta(2)-adrenergic receptor level in prostate cancer

Androgen deprivation is the only effective systemic therapy available for patients with prostatic carcinoma, but is associated with a gradual transition to a hormone‐refractory prostate cancer (HRCAP) in which ligand‐independent activation of the androgen receptor has been implicated. The β2‐adrenergic receptor (β2‐AR) is a well‐known activator of the androgen receptor.

TWIST1, A novel androgen-regulated gene, is a target for NKX3-1 in prostate cancer cells.

BackgroundTWIST1 plays a key role in EMT-mediated tumor invasion and metastasis. Since bone metastasis is a hallmark of advanced prostate cancer and is detected in at least 85% of patients who die of this disease, it is of great importance to understand the regulation of the cellular signaling pathways involved in the metastatic process.MethodsProstatic cell lines were analyzed using real time RT-PCR, chromatin immunoprecipitations (ChIP) and transfection of siRNA’s and reporter constructs.ResultsWe report in this paper that TWIST1 is an androgen-regulated gene under tight regulation of NKX3-1. Androgens repress the expression of TWIST1 via NKX3-1, which is a prostate–specific tumor suppressor that is down-regulated in the majority of metastatic prostate tumors. We show that NKX3-1 binds to the TWIST1 promoter and that NKX3-1 over-expression reduces the activity of a TWIST1 promoter reporter construct, whereas NKX3-1 siRNA up-regulates endogenous TWIST1 mRNA in prostate cancer cells.ConclusionOur finding that NKX3-1 represses TWIST1 expression emphasizes the functional importance of NKX3-1 in regulating TWIST1 expression during prostate cancer progression to metastatic disease.

PBX3 is a putative biomarker of aggressive prostate cancer

There is a great need to identify new and better prognostic and predictive biomarkers to stratify prostate cancer patients for optimal treatment. The aims of this study were to characterize the expression profile of pre‐B cell leukemia homeobox (PBX) transcription factors in prostate cancer with an emphasis on investigating whether PBX3 harbours any prognostic value. The expression profile of PBX3 and PBX1 in prostate tissue was determined by immunohistochemical and immunoblot analysis. Furthermore, the expression of PBX3 transcript variants was analyzed by RT‐PCR, NanoString Technologies®, and by analyzing RNA sequence data. The potential of PBX3 to predict prognosis, either at mRNA or protein level, was studied in four independent cohorts. PBX3 was mainly expressed in the nucleus of normal prostate basal cells, while it showed cytosolic expression in prostatic intraepithelial neoplasia and cancer cells. We detected four PBX3 transcript variants in prostate tissue. Competing risk regression analysis revealed that high PBX3 expression was associated with slower progression to castration resistant prostate cancer (sub‐hazard ratio (SHR) 0.18, 95% CI: 0.081–0.42, p values < 0.001). PBX3 expression had a high predictive accuracy (area under the curve (AUC) = 0.82) when combined with Gleason score and age. Patients undergoing radical prostatectomy, with high levels of PBX3 mRNA, had improved prostate cancer specific survival compared to patients expressing low levels (SHR 0.21, 95% CI: 0.46–0.93, p values < 0.001, and AUC = 0.75). Our findings strongly indicate that PBX3 has potential as a biomarker, both as part of a larger gene panel and as an immunohistochemical marker, for aggressive prostate cancer.