Use of nuclear androgen receptor status to predict early biochemical recurrence of prostate cancer patients

21073 Background: Prostate cancer (PCa) is a leading cause of cancer death in North American men. The androgen receptor (AR) has an established role in the progression of this disease; however, it is unclear at what stage it intervenes. It is also uncertain whether the AR can be a useful prognostic marker for PCa. In this study, we assessed AR expression and sub-cellular localization in normal prostate as well as in androgen sensitive and insensitive PCa (AIPCa) tissues, and evaluated the ability of the AR to predict biochemical recurrence (BCR). Methods: We used tissue micro-arrays containing prostate tissue cores obtained from cancer-free patients (n=43), AIPCa patients (n=36), and patients with hormone-sensitive cancers (n=64) from which were collected both cancerous and normal adjacent tissue. Using immmunohistochemistry, we stained the tissue micro-arrays with a monoclonal antibody recognizing the AR. Two observers assessed the frequency and intensity of both cytoplasmic and nuclear AR staining. AR cytoplasmic (Ci) and nuclear (Ni) indices were calculated by multiplying nuclear staining frequency and nuclear staining intensity. Kaplan Meier, and Cox multivariate analyses were done using SPSS. Results: We found that AR Ci increased significantly in AIPCa although a modest but significant increase in PCa Ci was observed compared to normal tissues. In contrast, AR Ni was significantly lower in cancer-free patients as opposed to that seen in normal tissue adjacent to cancer. Similarly, cancerous tissue exhibited higher AR Ni than its adjacent normal tissue (p<0.05, Kruskal-Wallis). Kaplan Meier analyses revealed that low AR Ni was predictive of an early onset of BCR (before 3-years) in the sub-cohort of hormone-sensitive patients (LR=6.51, p=0.011). Futhermore, low AR Ni remained an independent predictor of early BCR in a Cox multivariate model controlling for age, pre-operative PSA, lymph node invasion, Gleason score and surgical margin status (HR=2.28, 95% CI=1.04 - 5, p<0.05). Conclusions: We conclude that increased nuclear AR activity could be a pre-malignant step in PCa progression whereas its role within cancer cells may be more complex, as low AR nuclear activity was associated with early onset of BCR. No significant financial relationships to disclose.

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Nutlin3a Contributes to the Cytoplasmic Retention of Androgen Receptor

Proceedings ◽

10.3390/proceedings2251580 ◽

2018 ◽

Vol 2 (25) ◽

pp. 1580

Author(s):

Gulseren Ozduman ◽

Bilge Debelec Butuner ◽

Kemal Sami Korkmaz

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cellular Localization ◽

Nuclear Translocation ◽

Intracellular Localization ◽

Critical Role ◽

Cancer Therapeutics ◽

Luciferase Reporter ◽

Dependent Manner ◽

Normal Prostate

Prostate cancer cells need androgens to grow and maintain like normal prostate cells, both utilize that Androgen Receptor (AR) function. Androgen receptor (AR) is expressed throughout the prostate cancer progression plays a critical role as a transcription factor in castration-dependent stages of disease. AR also interacts to many cellular proteins, including p53, to regulate apoptosis. Further, as the stabilization of p53 protein triggers apoptosis, p53 interacting small molecules such as Nutlin3a, are interpreted as cancer therapeutics. In this study, to find out how Nutlin3a-mediated p53 stabilization effect on AR signaling. Here, we investigated the dynamics of p53 binding to transcriptional targets of AR, and further investigated the variations of AR intracellular localization as well as transactivation in the presence of Nutlin3a. To do this, the changes in AR transactivation were investigated via luciferase reporter assay, which was performed by treating LNCaPs with different doses of Nutlin3a and resulted that transactivation was suppressed by Nutlin3a in a dose dependent manner. AR transactivation and sub-cellular localization were also studied by immunofluorescence assay and found that cytoplasmic-nuclear fractionation-coupled western blot analysis showed that Nutlin3a inhibits AR phosphorylation and nuclear translocation regardless of androgens.

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Increased expression of androgen receptor (AR) and enzymes involved in androgen synthesis in metastatic prostate cancer: Targets for novel personalized therapies

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.5002 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 5002-5002

Author(s):

N. Mitsiades ◽

N. Schultz ◽

B. S. Taylor ◽

H. Hieronymus ◽

J. Satagopan ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

Androgen Receptor ◽

Normal Tissue ◽

Expression Profiles ◽

Prostate Tissue ◽

Steroidogenic Enzymes ◽

Normal Prostate ◽

Androgen Synthesis ◽

Normal Prostate Tissue

5002 Background: Androgen receptor (AR) signaling remains active in castration-resistant prostate cancer (CRPC) despite castrate levels of circulating androgens. This is indicated by continuous expression of androgen-responsive genes and is due to mechanisms that include: increased AR expression; AR mutations allowing promiscuous activation by alternative ligands; and increased intratumoral androgen levels, resulting from in situ steroidogenesis. Methods: Gene expression profiles of 30 normal prostate tissue samples, 131 primary prostate carcinomas (PCas) and 16 metastatic PCas, generated using Affymetrix Exon arrays, were interrogated for levels of 40 mRNAs encoding AR, SHBG, 28 enzymes involved in androgen synthesis and 10 enzymes involved in androgen inactivation. For individual tumors, a transcript was considered to be overexpressed or underexpressed when its levels were >2 SDs higher or lower, respectively, than its average levels in normal tissue. Results: Metastatic PCas expressed higher average transcript levels for AR and several steroidogenic enzymes, including SRD5A1 and SRD5A3, than primary PCas and normal prostate tissue. Expression of SRD5A2, CYP3A4, CYP3A5, and CYP3A7 mRNAs was decreased both in primary and metastatic tumors compared to normal prostate tissue. In analysis involving AR and 28 steroidogenic transcripts in individual tumors, all (16/16) metastatic PCas overexpressed at least one transcript (range: 2–14, median: 5 transcripts) compared to normal tissue, while 100/131 (76%) primary PCas overexpressed at least one transcript (range: 2–16, median: 2). Conclusions: Metastatic PCas overexpress AR and several steroidogenic enzymes, while they express lower levels of the androgen-inactivating enzymes CYP3A4, CYP3A5, and CYP3A7. These data highlight the role of AR and the androgen synthetic pathway as a therapeutic target in CRPC. Novel antiandrogens (MDV3100) and CYP17 inhibitors (abiraterone) are already in clinical trials in CRPC. Overexpression of AR or steroidogenic enzymes may serve as a biomarker (e.g. by detection via RT-PCR in circulating tumor cells) to predict for sensitivity to these agents and guide patient selection for participation in clinical trials. No significant financial relationships to disclose.

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Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells

Pharmaceuticals ◽

10.3390/ph14020103 ◽

2021 ◽

Vol 14 (2) ◽

pp. 103

Author(s):

Zohaib Rana ◽

Joel D. A. Tyndall ◽

Muhammad Hanif ◽

Christian G. Hartinger ◽

Rhonda J. Rosengren

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Hdac Inhibitors ◽

G1 Arrest ◽

Prostate Cancer Cells ◽

Prostate Tumors ◽

Normal Prostate ◽

Pc3 Cells ◽

Du145 Cells

Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.

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Down-regulation of Androgen Receptor by 3,3′-Diindolylmethane Contributes to Inhibition of Cell Proliferation and Induction of Apoptosis in Both Hormone-Sensitive LNCaP and Insensitive C4-2B Prostate Cancer Cells

Cancer Research ◽

10.1158/0008-5472.can-06-2011 ◽

2006 ◽

Vol 66 (20) ◽

pp. 10064-10072 ◽

Cited By ~ 76

Author(s):

Mohammad M.R. Bhuiyan ◽

Yiwei Li ◽

Sanjeev Banerjee ◽

Fakhara Ahmed ◽

Zhiwei Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Androgen Receptor ◽

Cancer Cells ◽

Prostate Cancer Cells ◽

Down Regulation ◽

Hormone Sensitive ◽

Induction Of Apoptosis

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Oligometastatic Disease Detection with 68Ga-PSMA-11 PET/CT in Hormone-Sensitive Prostate Cancer Patients (HSPC) with Biochemical Recurrence after Radical Prostatectomy: Predictive Factors and Clinical Impact

Cancers ◽

10.3390/cancers13194982 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4982

Author(s):

Carlos Artigas ◽

Romain Diamand ◽

Qaid Ahmed Shagera ◽

Nicolas Plouznikoff ◽

Fabrice Fokoue ◽

...

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Cancer Patients ◽

Predictive Factors ◽

Clinical Management ◽

Biochemical Recurrence ◽

Oligometastatic Disease ◽

Psma Pet ◽

Pet Ct ◽

Hormone Sensitive

Metastasis-directed therapy (MDT) in oligometastatic prostate cancer has the potential of delaying the start of androgen deprivation therapy (ADT) and disease progression. We aimed to analyze the efficacy of PSMA-PET/CT in detecting oligometastatic disease (OMD), to look for predictive factors of OMD, and to evaluate the impact of PSMA-PET/CT findings on clinical management. We retrospectively analyzed a homogeneous population of 196 hormone-sensitive prostate cancer patients (HSPC), considered potential candidates for MDT, with a PSMA-PET/CT performed at biochemical recurrence (BCR) after radical prostatectomy (RP). Multivariable logistic regression analysis was performed based on several clinico-pathological factors. Changes in clinical management before and after PSMA-PET/CT were analyzed. The OMD detection rate was 44% for a total positivity rate of 60%. PSMA-PET/CT positivity was independently related to PSA (OR (95%CI), p) (1.7 (1.3–2.3), p < 0.0001) and PSAdt (0.4 (0.2–0.8), p = 0.013), and OMD detection was independently related to PSA (1.6 (1.2–2.2), p = 0.001) and no previous salvage therapy (0.3 (0.1–0.9), p = 0.038). A treatment change was observed in 58% of patients, mostly to perform MDT after OMD detection (60% of changes). This study showed that PSMA-PET/CT is an excellent imaging technique to detect OMD early in HSPC patients with BCR after RP, changing therapeutic management mostly into MDT.

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The role of the androgen receptor as a driver and mitigator of cellular stress

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0057 ◽

2020 ◽

Vol 65 (2) ◽

pp. R19-R33

Author(s):

Dimitrios Doultsinos ◽

Ian Mills

Keyword(s):

Prostate Cancer ◽

Protein Synthesis ◽

Androgen Receptor ◽

Cancer Progression ◽

Prostate Gland ◽

Specific Antigen ◽

Nuclear Hormone Receptor ◽

Biological Processes ◽

Normal Prostate ◽

Mtor Activity

Prostate cancer is a high-incidence male cancer, which is dependent on the activity of a nuclear hormone receptor, the androgen receptor (AR). Since the AR is required for both normal prostate gland development and for prostate cancer progression, it is possible that prostate cancer evolves from perturbations in AR-dependent biological processes that sustain specialist glandular functions. The archetypal example of course is the use of prostate specific antigen (PSA), an organ-type specific component of the normal prostate secretome, as a biomarker of prostate cancer. Furthermore, localised prostate cancer is characterised by a low proliferative index and a heterogenous array of somatic mutations aligned to a multifocal disease pattern. We and others have identified a number of biological processes that are AR dependent and represent aberrations in significant glandular processes. Glands are characterised by high rates of metabolic activity including protein synthesis supported by co-dependent processes such as glycosylation, organelle biogenesis and vesicle trafficking. Impairments in anabolic metabolism and in protein folding/processing will inevitably impose proteotoxic and oxidative stress on glandular cells and, in particular, luminal epithelial cells for which secretion is their primary function. As cancer develops there is also significant metabolic dysregulation including impaired negative feedback effects on glycolytic and anabolic activity under conditions of hypoxia and heightened protein synthesis due to dysregulated PI 3-kinase/mTOR activity. In this review we will focus on the components of the AR regulome that support cancer development as well as glandular functions focussing on the unfolded protein response and on regulators of mTOR activity.

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Metabolic Roles of Androgen Receptor and Tip60 in Androgen-Dependent Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21186622 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6622

Author(s):

Kah Ni Tan ◽

Vicky M. Avery ◽

Catalina Carrasco-Pozo

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Cell Fate ◽

Tricarboxylic Acid Cycle ◽

Mammalian Target Of Rapamycin ◽

Hypoxia Inducible Factor ◽

Normal Prostate ◽

Calcium Calmodulin Dependent ◽

Metabolic Regulators

Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer.

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Increased Cytoplasmic CD138 Expression Is Associated with Aggressive Characteristics in Prostate Cancer and Is an Independent Predictor for Biochemical Recurrence

BioMed Research International ◽

10.1155/2020/5845374 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Simon Kind ◽

Martina Kluth ◽

Claudia Hube-Magg ◽

Katharina Möller ◽

Georgia Makrypidi-Fraune ◽

...

Keyword(s):

Prostate Cancer ◽

Biochemical Recurrence ◽

Independent Predictor ◽

Surgical Margin ◽

Tumor Stage ◽

Positive Surgical Margin ◽

Gleason Grade ◽

Basal Cells ◽

Antibody Drug Conjugate ◽

Normal Prostate

Syndecan-1 (CD138) is a transmembrane proteoglycan expressed in various normal and malignant tissues. It is of interest due to a possible prognostic effect in tumors and its role as a target for the antibody-drug conjugate indatuximab ravtansine. Here, we analyzed 17,747 prostate cancers by immunohistochemistry. Membranous and cytoplasmic CD138 staining was separately recorded. In normal prostate glands, CD138 staining was limited to basal cells. In cancers, membranous CD138 positivity was seen in 19.6% and cytoplasmic CD138 staining in 11.2% of 12,851 interpretable cases. A comparison with clinico-pathological features showed that cytoplasmic CD138 staining was more linked to unfavorable tumor features than membranous staining. Cytoplasmic CD138 immunostaining was associated with high tumor stage ( p < 0.0001 ), high Gleason grade ( p < 0.0001 ), nodal metastases ( p < 0.0001 ), positive surgical margin ( p < 0.0001 ), and biochemical recurrence ( p < 0.0001 ). This also holds true for both V-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion positive and ERG fusion negative tumors although the cytoplasmic CD138 expression was markedly more frequent in ERG positive than in ERG negative tumors ( p < 0.0001 ). Comparison with 11 previously analyzed chromosomal deletions identified a conspicuous association between cytoplasmic CD138 expression and 8p deletions ( p < 0.0001 ) suggesting a possible functional interaction of CD138 with one or several 8p genes. Multivariate analysis revealed the cytoplasmic CD138 expression as an independent prognostic parameter in all cancers and in the ERG positive subgroup. In summary, our study indicates the cytoplasmic CD138 expression as a strong and independent predictor of poor prognosis in prostate cancer. Immunohistochemical measurement of CD138 protein may thus—perhaps in combination with other parameters—become clinically useful in the future.

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