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Androgen Receptor Phosphorylation at Serine 308 and Serine 791 Predicts Enhanced Survival in Castrate Resistant Prostate Cancer Patients  [PDF]
Pamela McCall,Claire E. Adams,Jennifer M. Willder,Lindsay Bennett,Tahir Qayyum,Clare Orange,Mark A. Underwood,Joanne Edwards
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140816656
Abstract: We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone na?ve prostate cancer (HNPC) to castrate resistant disease (CRPC). A panel of phosphospecific antibodies were employed to study AR phosphorylation in 84 matched HNPC and CRPC tumours. Immunohistochemistry measured Androgen receptor expression phosphorylated at serine residues 94 (pAR 94), 308 (pAR 308), 650(pAR 650) and 791 (pAR 791). No correlations with clinical parameters were observed for pAR 94 or pAR 650 in HNPC or CRPC tumours. In contrast to our previous observation with serine 213, high pAR 308 is significantly associated with a longer time to disease specific death ( p = 0.011) and high pAR 791 expression significantly associated with a longer time to disease recurrence ( p = 0.018) in HNPC tumours and longer time to death from disease recurrence ( p = 0.040) in CRPC tumours. This observation in CRPC tumours was attenuated in high apoptotic tumours ( p = 0.022) and low proliferating tumours ( p = 0.004). These results demonstrate that understanding the differing roles of AR phosphorylation is necessary before this can be exploited as a target for castrate resistant prostate cancer.
New Insights into the Androgen-Targeted Therapies and Epigenetic Therapies in Prostate Cancer  [PDF]
Abhijit M. Godbole,Vincent C. O. Njar
Prostate Cancer , 2011, DOI: 10.1155/2011/918707
Abstract: Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The androgen receptor (AR), a receptor of nuclear family and a transcription factor, is the most important target in this disease. While most efforts in the clinic are currently directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops. Most prostate cancer deaths are attributable to this castration-resistant form of prostate cancer (CRPC). Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes, posttranslational modifications of AR such as sumoylation. Herein, we provide an overview of the structure of human AR and its key structural domains that can be used as targets to develop novel antiandrogens. We also summarize recent findings about the antiandrogens and the epigenetic factors that modulate the action of AR. 1. Introduction Prostate cancer (PC) is the second most prevalent cause of death in men in the USA and Europe. The dependence of PC on androgens has been recognized for more than 7 decades. Medical and surgical androgen deprivation therapy (ADT) has been a standard palliative therapy for metastatic PC. However, an estimated 217,730 new cases and 32,050 PC-related deaths in the USA alone in 2010 despite ADT [1] make the need for finding new targets and novel therapies an absolute priority. Androgen, the male steroid hormone, is responsible for male sexual differentiation and development, as well as the maintenance and support of sexual tissues in the adult. Moreover, androgens are important for the development and progression of age-associated pathologies in men, including benign prostatic hyperplasia and prostate cancer (PC). Androgen action is exerted through the androgen receptor (AR), a 110-kDa member of the steroid receptor family of transcription factors [2]. The physiological ligands for the AR are testosterone and dihydrotestosterone (DHT). The later has at least 10-fold stronger binding affinity. The most commonly used therapies in metastatic prostate cancer involve androgen deprivation through medical (LHRH agonists), surgical castration, or disruption of androgen binding to AR [3]. Such treatments are temporarily effective, but, over time, most prostate cancers evolve into a castration-resistant state [4, 5]. Resistance mechanisms include AR, gene mutation or amplification, ligand independent activation of AR and persistent intraprostatic androgens [6–8].
Tumor-Specific Hypermethylation of Epigenetic Biomarkers, Including SFRP1, Predicts for Poorer Survival in Patients from the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) Project  [PDF]
Christopher J. Ricketts, Victoria K. Hill, W. Marston Linehan
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0085621
Abstract: The recent publication of the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) project has provided an immense wealth and breadth of data providing an invaluable tool for confirmation and expansion upon previous observations in a large data set containing multiple data types including DNA methylation, somatic mutation, and clinical information. In clear cell renal cell carcinoma (CCRCC) many genes have been demonstrated to be epigenetically inactivated by promoter hypermethylated and in a small number of cases to be associated with clinical outcome. This study created two cohorts based on the Illumina BeadChip array used to confirm the frequency of tumor-specific hypermethylation of these published hypermethylated genes, assess the impact of somatic mutation or chromosomal loss and provide the most comprehensive assessment to date of the association of this hypermethylation with patient survival. Hypermethylation of the Fibrillin 2 (FBN2) gene was the most consistent epigenetic biomarker for CCRCC across both cohorts in 40.2% or 52.5% of tumors respectively. Hypermethylation of the secreted frizzled-related protein 1 (SFRP1) gene and the basonuclin 1 (BNC1) gene were both statistically associated with poorer survival in both cohorts (SFRP1 - p = <0.0001 or 0.0010 and BNC1 - p = <0.0001 or 0.0380) and represented better independent markers of survival than tumor stage, grade or dimension in one cohort and tumor stage or dimension in the other cohort. Loss of the SFRP1 protein can potentially activate the WNT pathway and this analysis highlighted hypermethylation of several other WNT pathway regulating genes and demonstrated a poorer survival outcome for patients with somatic mutation of these genes. The success of demethylating drugs in hematological malignances and the current trials in solid tumors suggest that the identification of clinically relevant hypermethylated genes combined with therapeutic advances may improve the effectiveness and usefulness of such drugs in clear cell renal cell carcinoma.
The Impact of Androgen Receptor Expression on Breast Cancer Survival: A Retrospective Study and Meta-Analysis  [PDF]
Qing Qu, Yan Mao, Xiao-chun Fei, Kun-wei Shen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082650
Abstract: Recent studies have highlighted the role of androgen receptor (AR) as a prognostic biomarker of breast cancer. However, its predictive role in disease free survival (DFS) and overall survival (OS) still remains inconclusive. The present study aimed to retrospectively investigate the association between AR and survival outcomes in breast cancer and also identify this association by a meta-analysis of published researches. Clinical data from 109 patients with breast cancer, who underwent surgery at Ruijin Hospital, Shanghai, were retrospectively analyzed for immunohistochemical AR expression measured by tissue microarray. For meta-analysis, articles available in Pubmed on the relationship between AR and breast cancer outcomes were included. Data obtained from both were combined and analyzed. Women with AR positive tumors in the retrospective study had a significantly better DFS (HR 0.24, 95% CI 0.07-0.88) and OS (HR 0.19, 95% CI 0.04-0.85) than women with AR negative ones. Meta-analysis showed that AR expression in breast tumors was an indicator of better DFS (HR 0.52, 95% CI 0.43-0.64). In subgroup analysis, AR could predict DFS outcome in estrogen receptor (ER) positive (HR 0.45, 95% CI 0.34-0.59), ER negative (HR 0.42, 95% CI 0.26-0.67), and triple negative breast cancer (HR 0.40, 95% CI 0.23-0.69). Moreover, in ER positive breast cancer patients, the expression of AR could predict better OS (HR 0.39, 95% CI 0.19-0.82). The present analysis indicated that AR expression was associated with lower risk of recurrence in patients with all breast cancer types and better OS in cases with ER positive.
Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival
Qing Yang, Kar-Ming Fung, Wanda V Day, Bradley P Kropp, Hsueh-Kung Lin
Cancer Cell International , 2005, DOI: 10.1186/1475-2867-5-8
Abstract: The siRNA design successfully suppressed endogenous AR expression, as revealed by western blotting and immunofluorescence staining in LNCaP cells. LNCaP cells did not proliferate in the absence of AR and underwent apoptosis, based on elevated phospho-Histone H2B expression and higher number of apoptotic body as compared to control cells.We demonstrated that AR is vital for prostate cell proliferation and survival in this androgen-sensitive prostate cell line. These results further strengthen the hypothesis that AR can be a therapeutic target for treating androgen-sensitive stages of PCa. Unlike antiandorgens, however, siRNA targeting AR provides a direct inactivation of AR function through the suppression of AR protein expression.Androgens are critical for the development and growth of normal prostate. They also are responsible for the development of prostate diseases, including benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Androgen receptors (AR) transduce androgen signals in prostate cells to regulate the physiological and pathological development of the gland [1]. It is classically characterized that after ligand binding [mainly 5α-dihydrotestosterone (5α-DHT)] the ligand-AR receptor complex with associated proteins translocates into the nucleus, binds to the consensus sequence of androgen response elements (AREs) [2], and regulates androgen responsive genes (ARGs) expressions [3]. Conditions that activate abnormal AR trans-activation through AR mutations [4,5], amplification of AR [6], or androgen-independent signaling pathways [7,8] can lead to or be a result of the development of prostatic diseases or androgen refractory PCa.Clinically, androgen ablation therapy is used to reduce AR ligand production or to block AR-mediated signaling. Finasteride, a 5α-reductase type 2 inhibitor, has been used for treating patients with BPH. Finasteride slows the progression of BPH by suppressing 5α-DHT synthesis [9]. Androgen ablation therapy for PCa has been
Androgen receptors as a prognostic and predictive factor in breast cancer.  [cached]
Anil K Agrawal,Micha? Jeleń,Zygmunt Grzebieniak,Piotr Zukrowski
Folia Histochemica et Cytobiologica , 2008, DOI: 10.5603/4415
Abstract: Many theoretical and experimental models indicate that androgen receptors can play an important role as prognostic factors in breast cancer. The aim of this study was to evaluate the correlations between the presence of androgen receptors on cancer cells and other selected prognostic and predictive factors with established clinical significance in women with breast cancer after radical surgical treatment. 488 adult females were included in the study, who underwent primary radical surgery for breast cancer. 428 patients (87.7%) had Patey's conservative radical mastectomy and 60 (12.3%) Halsted's radical mastectomy. The mean age at operation was 54.3, ranging from 32 to 79. The mean length of hospitalization was 7.2 days for the patients after Patey's mastectomy and 9.8 days for those after Halsted's mastectomy. The androgen receptor is the most frequently detected steroid receptor on breast cancer cells. Therapeutic efficacy of adjuvant hormone therapy was higher in the group of androgen receptor-positive patients than in androgen receptor-negative ones. The prognosis for androgen receptor-positive patients who underwent adjuvant hormone therapy was better than for those androgen receptor-positive patients who did not receive hormone therapy after primary radical surgery for breast cancer. Assessment of androgen receptor levels on cancer cells should become a routine procedure with patients undergoing primary radical surgery for breast cancer, as it seems to be an important predictive factor.
Androgen Receptor Status Is a Prognostic Marker in Non-Basal Triple Negative Breast Cancers and Determines Novel Therapeutic Options  [PDF]
Pierluigi Gasparini, Matteo Fassan, Luciano Cascione, Gulnur Guler, Serdar Balci, Cigdem Irkkan, Carolyn Paisie, Francesca Lovat, Carl Morrison, Jianying Zhang, Aldo Scarpa, Carlo M. Croce, Charles L. Shapiro, Kay Huebner
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088525
Abstract: Triple negative breast cancers are a heterogeneous group of tumors characterized by poor patient survival and lack of targeted therapeutics. Androgen receptor has been associated with triple negative breast cancer pathogenesis, but its role in the different subtypes has not been clearly defined. We examined androgen receptor protein expression by immunohistochemical analysis in 678 breast cancers, including 396 triple negative cancers. Fifty matched lymph node metastases were also examined. Association of expression status with clinical (race, survival) and pathological (basal, non-basal subtype, stage, grade) features was also evaluated. In 160 triple negative breast cancers, mRNA microarray expression profiling was performed, and differences according to androgen receptor status were analyzed. In triple negative cancers the percentage of androgen receptor positive cases was lower (24.8% vs 81.6% of non-triple negative cases), especially in African American women (16.7% vs 25.5% of cancers of white women). No significant difference in androgen receptor expression was observed in primary tumors vs matched metastatic lesions. Positive androgen receptor immunoreactivity was inversely correlated with tumor grade (p<0.01) and associated with better overall patient survival (p = 0.032) in the non-basal triple negative cancer group. In the microarray study, expression of three genes (HER4, TNFSF10, CDK6) showed significant deregulation in association with androgen receptor status; eg CDK6, a novel therapeutic target in triple negative cancers, showed significantly higher expression level in androgen receptor negative cases (p<0.01). These findings confirm the prognostic impact of androgen receptor expression in non-basal triple negative breast cancers, and suggest targeting of new androgen receptor-related molecular pathways in patients with these cancers.
Androgen Receptor Function Links Human Sexual Dimorphism to DNA Methylation  [PDF]
Ole Ammerpohl, Susanne Bens, Mahesh Appari, Ralf Werner, Bernhard Korn, Stenvert L. S. Drop, Frans Verheijen, Yvonne van der Zwan, Trevor Bunch, Ieuan Hughes, Martine Cools, Felix G. Riepe, Olaf Hiort, Reiner Siebert, Paul-Martin Holterhus
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073288
Abstract: Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS) due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aberrant androgen receptor function is associated with distinct patterns of DNA-methylation marks in genital tissues. These findings support the concept that transcription factor binding to the DNA has an impact on the shape of the DNA methylome. These data which derived from a rare human model suggest that androgen programming of methylation marks contributes to sexual dimorphism in the human which might have considerable impact on the manifestation of sex-associated phenotypes and diseases.
Expression and Function of Androgen Receptor Coactivator p44/Mep50/WDR77 in Ovarian Cancer  [PDF]
Martin Ligr, Ruzeen Rohintan Patwa, Garrett Daniels, Lorraine Pan, Xinyu Wu, Yirong Li, Liantian Tian, Zhenxing Wang, Ruliang Xu, Jingjing Wu, Fan Chen, Jinsong Liu, Jian-Jun Wei, Peng Lee
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026250
Abstract: Hormones, including estrogen and progesterone, and their receptors play an important role in the development and progression of ovarian carcinoma. Androgen, its receptor and coactivators have also been implicated in these processes. p44/Mep50/WDR77 was identified as a subunit of the methylosome complex and lately characterized as a steroid receptor coactivator that enhances androgen receptor as well as estrogen receptor-mediated transcriptional activity in a ligand-dependent manner. We previously described distinct expression and function of p44 in prostate, testis, and breast cancers. In this report, we examined the expression and function of p44 in ovarian cancer. In contrast to findings in prostate and testicular cancer and similar to breast cancer, p44 shows strong cytoplasmic localization in morphologically normal ovarian surface and fallopian tube epithelia, while nuclear p44 is observed in invasive ovarian carcinoma. We observed that p44 can serve as a coactivator of both androgen receptor (AR) and estrogen receptor (ER) in ovarian cells. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in ovarian cancer cells in the presence of estrogen or androgen. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during ovarian tumorigenesis.
Severe forms of partial androgen insensitivity syndrome due to p.L830F novel mutation in androgen receptor gene in a Brazilian family
Reginaldo J Petroli, Andréa T Maciel-Guerra, Fernanda C Soardi, Flávia L de Calais, Gil Guerra-Junior, Maricilda de Mello
BMC Research Notes , 2011, DOI: 10.1186/1756-0500-4-173
Abstract: Molecular abnormalities in the androgen receptor gene in individuals of a Brazilian family with clinical features of severe forms of partial androgen insensitivity syndrome were evaluated. Seven members (five 46,XY females and two healthy mothers) of the family were included in the investigation. The coding exons and exon-intron junctions of androgen receptor gene were sequenced. Five 46,XY members of the family have been found to be hemizygous for the c.3015C>T nucleotide change in exon 7 of the androgen receptor gene, whereas the two 46,XX mothers were heterozygote carriers. This nucleotide substitution leads to the p.L830F mutation in the androgen receptor.The novel p.L830F mutation is responsible for grades 5 and 6 of partial androgen insensitivity syndrome in two generations of a Brazilian family.The androgen insensitivity syndrome (AIS, OMIN #300068) is a recessive disorder linked to the X chromosome. It may result in the failure of external genitalia masculinization in individuals with 46,XY karyotype and normal androgen production and metabolism [1,2]. There is a wide range of clinical manifestation, therefore the syndrome can be divided in three subgroups according the degree of undermasculinization: 1) mild AIS (MAIS) that is characterized by gynecomastia and infertility in phenotypically male individuals; 2) partial AIS (PAIS) that may present with predominantly male development or ambiguous genitalia (AG) or even with predominantly female external genitalia with clitoromegaly and/or posterior labial fusion and breast and pubic hair development; 3) complete AIS (CAIS) resulting in female external genitalia, sparse to absent pubic and axilary hair and normal breast development [2-6]. Due to significant differences generally found among clinical manifestation features in PAIS, some authors assigned grades ranging from 1 to 6 to describe patients that presented with different phenotypes varying from male genitalia and infertility to female genitalia with pub
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