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Transcription factors involved in prostate gland adaptation to androgen deprivation.

ABSTRACT: Androgens regulate prostate physiology, and exert their effects through the androgen receptor. We hypothesized that androgen deprivation needs additional transcription factors to orchestrate the changes taking place in the gland after castration and for the adaptation of the epithelial cells to the androgen-deprived environment, ultimately contributing to the origin of castration-resistant prostate cancer. This study was undertaken to identify transcription factors that regulate gene expression after androgen deprivation by castration (Cas). For the sake of comparison, we extended the analysis to the effects of administration of a high dose of 17?-estradiol (E2) and a combination of both (Cas+E2). We approached this by (i) identifying gene expression profiles and enrichment terms, and by searching for transcription factors in the derived regulatory pathways; and (ii) by determining the density of putative transcription factor binding sites in the proximal promoter of the 10 most up- or down-regulated genes in each experimental group in comparison to the controls Gapdh and Tbp7. Filtering and validation confirmed the expression and localized EVI1 (Mecom), NFY, ELK1, GATA2, MYBL1, MYBL2, and NFkB family members (NFkB1, NFkB2, REL, RELA and RELB) in the epithelial and/or stromal cells. These transcription factors represent major regulators of epithelial cell survival and immaturity as well as an adaptation of the gland as an immune barrier in the absence of functional stimulation by androgens. Elk1 was expressed in smooth muscle cells and was up-regulated after day 4. Evi1 and Nfy genes are expressed in both epithelium and stroma, but were apparently not affected by androgen deprivation.

SUBMITTER: Rosa-Ribeiro R

PROVIDER: S-EPMC4041569 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Transcription factors involved in prostate gland adaptation to androgen deprivation.

Rosa-Ribeiro Rafaela R Nishan Umar U Vidal Ramon Oliveira RO Barbosa Guilherme Oliveira GO Reis Leonardo Oliveira LO Cesar Carlos Lenz CL Carvalho Hernandes F HF

PloS one 20140602 6

Androgens regulate prostate physiology, and exert their effects through the androgen receptor. We hypothesized that androgen deprivation needs additional transcription factors to orchestrate the changes taking place in the gland after castration and for the adaptation of the epithelial cells to the androgen-deprived environment, ultimately contributing to the origin of castration-resistant prostate cancer. This study was undertaken to identify transcription factors that regulate gene expression ...[more]

PMID: 24886974

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Project description:Androgens are required for prostate development, growth and physiology, by activating the androgen receptor (AR) upon activation by testosterone and dihydrotestosterone (DHT), the AR undergoes conformational changes, dimerizes and translocates to the cell nucleus regulation important genes releted to cell survival. Understanding the mechanisms of androgen regulation in the prostate gland is important, because the prostate is affected by several different diseases, in particular prostate cancer (PCa). Several ways exist to treat prostate cancer and promote epithelial cell death. Treatments involving androgen manipulation include surgical castration (bilateral orchiectomy), antiandrogens (usually AR antagonists), or substances that inhibit androgen synthesis (5 alpha-reductase inhibitors, gonadotrophin-releasing hormone blockers). 17 beta-estradiol exerts anti-androgen effects by blocking the hypothalamic production of gonadotropin-releasing hormone and thereby inhibiting the production of testosterone by the testes , but also acts locally via interactions with either of the estrogen receptors found in the gland. It is known that the kinetics of apoptosis are different in the rat ventral prostate (VP) of castrated rats (Cas group) and in rats subjected to 17 beta-estradiol high dose (group E2) or their combination (group Cas+E2), with an evident additive effect in the latter situation (Garcia-Florez et al, 2005). The microarray approach was done to figure out what genes are expressed and how the cells of ventral prostate gland responses when the androgen is not available comparing three diferent androgen deprivation methods (sirurgical castration, high dose of 17-beta estradiol and both treatment combined). Forty-eight 21-day-old male Wistar rats were obtained from the Multidisciplinary Center for Biological Research (CEMIB), University of Campinas. The animals were kept under normal light conditions (12-h light:dark cycle) and received filtered tap water and Purina rodent chow ad libitum. On the 90th day after birth, the rats were divided in four groups (n=3) and assigned to different treatment groups. To cause androgen deprivation, we utilized three different procedures with different effects on epithelial cell apoptosis. Animals in the first group were castrated (Cas) by orchiectomy via scrotal incision under ketamine (150 mg/Kg body weight) and xylazin (10 mg/kg body weight) anesthesia. Animals in the second group received a 25 mg/Kg body weight dose of 17β-estradiol diluted in corn oil (E2 group). The third group received a combination of both treatments (Cas+E2 group) (combined orchiectomy and 17β-estradiol). In the control group (Ct; normal androgen and estrogen), the animals received only the vehicle. Three days after the treatments, the rats were killed by anesthetic overdose, and the ventral prostate was dissected out for the microarray and immunohistochemistry analyses.

Project description:BackgroundCastration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence.MethodsMen with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization.ResultsA total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events.ConclusionsOur findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).

Project description:ContextAndrogen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk-benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease.ObjectiveReview the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds.Evidence acquisitionA comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated.Evidence synthesisData from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone-releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality.ConclusionsAlthough ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk-benefit ratio.

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Transcription factors involved in prostate gland adaptation to androgen deprivation.

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Transcription factors involved in prostate gland adaptation to androgen deprivation.

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