Objectives: To evaluate the androgen receptor (AR) gene copy number in androgen deprivation therapy (ADT) treatment-naïve prostate cancer (PCa) patients and to evaluate the corresponding AR protein expression and assess the association between these features and prognostic factors. Materials and Methods: Chromosome X and AR gene copy number, using fluorescence-in-situ-hybridization, and epithelial-stromal AR expression, using AR immunohistochemistry, were analyzed in 62 ADT treatment-naïve PCa patients and 8 castration-refractory patients. Results: In ADT treatment-naïve PCa patients, the AR expression was higher in tumor epithelial cells versus surrounding stromal cells (p < 0.001) and versus normal epithelium in the same patient (p = 0.043). The difference between tumoral AR expression and expression in normal epithelium was higher in patients with ≥15% of tumor cells with increased AR copy number (p = 0.019). Peritumoral stroma had lower AR expression in patients with lymph-node or distant metastases compared to those without metastases (p = 0.038). Conclusions: This research evaluates the link between AR gene status, expression profile, and possible prognostic factors. Furthermore, it highlights the importance of the peritumoral environment in PCa. Additional research is needed to further clarify the role of stromal AR in PCa dissemination and identify possible therapeutic strategies to target this mechanism.

Keywords:
Androgen receptor, Gene amplification, Prostate cancer, Protein expression, X chromosome
1.
Saraon P, Jarvi K, Diamandis EP: Molecular alterations during progression of prostate cancer to androgen independence. Clin Chem 2011;57:1366-1375.
2.
Edwards J, Krishna NS, Grigor KM, Bartlett JM: Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer 2003;89:552-556.
3.
Ford OH 3rd, Gregory CW, Kim D, Smitherman AB, Mohler JL: Androgen receptor gene amplification and protein expression in recurrent prostate cancer. J Urol 2003;170:1817-1821.
4.
Haapala K, Kuukasjärvi T, Hyytinen E, Rantala I, Helin HJ, Koivisto PA: Androgen receptor amplification is associated with increased cell proliferation in prostate cancer. Hum Pathol 2007;38:474-478.
5.
Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, Trapman J, Cleutjens K, Noordzij A, Visakorpi T, Kallioniemi OP: Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res 1997;57:314-319.
6.
Miyoshi Y, Uemura H, Fujinami K, Mikata K, Harada M, Kitamura H, Koizumi Y, Kubota Y: Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients. Prostate 2000;43:225-232.
7.
Ropke A, Erbersdobler A, Hammerer P, Palisaar J, John K, Stumm M, Wieacker P: Gain of androgen receptor gene copies in primary prostate cancer due to X chromosome polysomy. Prostate 2004;59:59-68.
8.
Leake R, Barnes D, Pinder S, Ellis I, Anderson L, Anderson T, Adamson R, Rhodes T, Miller K, Walker R: Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. UK Receptor Group, UK NEQAS, The Scottish Breast Cancer Pathology Group, and The Receptor and Biomarker Study Group of the EORTC. J Clin Pathol 2000;53:634-635.
9.
Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, Quist MJ, Jing X, Lonigro RJ, Brenner JC, Asangani IA, Ateeq B, Chun SY, Siddiqui J, Sam L, Anstett M, Mehra R, Prensner JR, Palanisamy N, Ryslik GA, Vandin F, Raphael BJ, Kunju LP, Rhodes DR, Pienta KJ, Chinnaiyan AM, Tomlins SA: The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012;487:239-243.
10.
Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi OP: In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995;9:401-406.
11.
Beltran H, Eng K, Mosquera JM, Sigaras A, Romanel A, Rennert H, Kossai M, Pauli C, Faltas B, Fontugne J, Park K, Banfelder J, Prandi D, Madhukar N, Zhang T, Padilla J, Greco N, McNary TJ, Herrscher E, Wilkes D, MacDonald TY, Xue H, Vacic V, Emde AK, Oschwald D, Tan AY, Chen Z, Collins C, Gleave ME, Wang Y, Chakravarty D, Schiffman M, Kim R, Campagne F, Robinson BD, Nanus DM, Tagawa ST, Xiang JZ, Smogorzewska A, Demichelis F, Rickman DS, Sboner A, Elemento O, Rubin MA: Whole-exome sequencing of metastatic cancer and biomarkers of treatment response. JAMA Oncol 2015;1:466-474.
12.
Zhang X, Hong SZ, Lin EJ, Wang DY, Li ZJ, Chen LI: Amplification and protein expression of androgen receptor gene in prostate cancer cells: fluorescence in situ hybridization analysis. Oncol Lett 2015;9:2617-2622.
13.
Merson S, Yang ZH, Brewer D, Olmos D, Eichholz A, McCarthy F, Fisher G, Kovacs G, Berney DM, Foster CS, Møller H, Scardino P, Cuzick J, Cooper CS, Clark JP: Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer. Br J Cancer 2014;110:1655-1662.
14.
Cano P, Godoy A, Escamilla R, Dhir R, Onate SA: Stromal-epithelial cell interactions and androgen receptor-coregulator recruitment is altered in the tissue microenvironment of prostate cancer. Cancer Res 2007;67:511-519.
15.
Ricciardelli C, Choong CS, Buchanan G, Vivekanandan S, Neufing P, Stahl J, Marshall VR, Horsfall DJ, Tilley WD: Androgen receptor levels in prostate cancer epithelial and peritumoral stromal cells identify non-organ confined disease. Prostate 2005;63:19-28.
16.
Wikström P, Marusic J, Stattin P, Bergh A: Low stroma androgen receptor level in normal and tumor prostate tissue is related to poor outcome in prostate cancer patients. Prostate 2009;69:799-809.
17.
Dakhova O, Ozen M, Creighton CJ, Li R, Ayala G, Rowley D, Ittmann M: Global gene expression analysis of reactive stroma in prostate cancer. Clin Cancer Res 2009;15:3979-3989.
18.
Yanagisawa N, Li R, Rowley D, Liu H, Kadmon D, Miles BJ, Wheeler TM, Ayala GE: Reprint of: stromogenic prostatic carcinoma pattern (carcinomas with reactive stromal grade 3) in needle biopsies predicts biochemical recurrence-free survival in patients after radical prostatectomy. Hum Pathol 2008;39:282-291.
19.
Ayala GE, Muezzinoglu B, Hammerich KH, Frolov A, Liu H, Scardino PT, Li R, Sayeeduddin M, Ittmann MM, Kadmon D, Miles BJ, Wheeler TM, Rowley DR: Determining prostate cancer-specific death through quantification of stromogenic carcinoma area in prostatectomy specimens. Am J Pathol 2011;178:79-87.
20.
Lai KP, Yamashita S, Huang CK, Yeh S, Chang C: Loss of stromal androgen receptor leads to suppressed prostate tumourigenesis via modulation of pro-inflammatory cytokines/chemokines. EMBO Mol Med 2012;4:791-807.
21.
Lu YY, Jiang B, Zhao FJ, Cui D, Jiang Q, Yu JJ, Li EH, Wang XH, Han BM, Xia SJ: Androgen receptors expressed by prostatic stromal cells obtained from younger versus older males exhibit opposite roles in prostate cancer progression. Asian J Androl 2013;15:672-678.
22.
Singh M, Jha R, Melamed J, Shapiro E, Hayward SW, Lee P: Stromal androgen receptor in prostate development and cancer. Am J Pathol 2014;184:2598-2607.
23.
Fujimura T, Takahashi S, Urano T, Takayama K, Sugihara T, Obinata D, Yamada Y, Kumagai J, Kume H, Ouchi Y, Inoue S, Homma Y: Expression of androgen and estrogen signaling components and stem cell markers to predict cancer progression and cancer-specific survival in patients with metastatic prostate cancer. Clin Cancer Res 2014;20:4625-4635.
24.
Henshall SM, Quinn DI, Lee CS, Head DR, Golovsky D, Brenner PC, Delprado W, Stricker PD, Grygiel JJ, Sutherland RL: Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer. Cancer Res 2001;61:423-427.
25.
Poelaert F, Van Praet C, Beerens AS, De Meerleer G, Fonteyne V, Ost P, Lumen N: The role of androgen receptor expression in the curative treatment of prostate cancer with radiotherapy: a pilot study. Biomed Res Int 2015;2015:812815.
26.
Li R, Wheeler T, Dai H, Frolov A, Thompson T, Ayala G: High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate: cancer patients treated with radical prostatectomy. Am J Surg Pathol 2004;28:928-934.
27.
Tamburrino L, Salvianti F, Marchiani S, Pinzani P, Nesi G, Serni S, Forti G, Baldi E: Androgen receptor (AR) expression in prostate cancer and progression of the tumor: lessons from cell lines, animal models and human specimens. Steroids 2012;77:996-1001.
28.
Olapade-Olaopa EO, MacKay EH, Taub NA, Sandhu DP, Terry TR, Habib FK: Malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor immunoreactivity in the surrounding stroma. Clin Cancer Res 1999;5:569-576.
29.
Tanner MJ, Welliver RC Jr, Chen M, Shtutman M, Godoy A, Smith G, Mian BM, Buttyan R: Effects of androgen receptor and androgen on gene expression in prostate stromal fibroblasts and paracrine signaling to prostate cancer cells. PLoS One 2011;6:e16027.
30.
Zhifang M, Liang W, Wei Z, Bin H, Rui T, Nan W, Shuhai Z: The androgen receptor plays a suppressive role in epithelial-mesenchymal transition of human prostate cancer stem progenitor cells. BMC Biochem 2015;16:13.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.