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Erschienen in: Endocrine 2/2018

19.07.2018 | Original Article

Androgenic modulation of AR-Vs

verfasst von: Ana Caroline Hillebrand, Lolita Schneider Pizzolato, Gisele Branchini, Ilma Simoni Brum

Erschienen in: Endocrine | Ausgabe 2/2018

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Abstract

Purpose

The importance of androgen receptor variants (AR-Vs) is recognized in prostate cancer. AR-Vs have been the focus of many studies. Expression of AR-Vs has been proposed as a biomarker for resistance to androgen deprivation therapy for metastatic disease. Herein, we show dynamic changes in AR-Vs expression in response to androgen modulation.

Methods

The C4-2B cell line was exposed to low (10−13 M) and high (10−8 M) androgen (dihydrotestosterone, DHT) levels, with or without flutamide. mRNA and protein expression levels were assessed by qPCR and immunohistochemistry, respectively.

Results

We demonstrated that high levels of DHT downregulate AR-FL and AR-Vs. Even though AR-Vs did not present ligand-binding domain, thus were not capable of binding to DHT, they present dynamic changes under androgen treatment. Treatment with flutamide alone or in association with low levels of DHT stimulates growth of prostatic cells.

Conclusions

Importantly, we provide evidence that AR-Vs respond differently to androgenic modulation. These findings have implications for a better understanding of the role of AR-Vs in prostate carcinogenesis.
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Literatur
1.
Zurück zum Zitat C. Carson 3rd, R. Rittmaster, The role of dihydrotestosterone in benign prostatic hyperplasia. Urology 61(4 Suppl 1), 2–7 (2003)CrossRef C. Carson 3rd, R. Rittmaster, The role of dihydrotestosterone in benign prostatic hyperplasia. Urology 61(4 Suppl 1), 2–7 (2003)CrossRef
3.
Zurück zum Zitat C. Huggins, C.V. Hodges, Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J. Urol. 168(1), 9–12 (2002). https://doi.org/S0022-5347(05)64820-3CrossRef C. Huggins, C.V. Hodges, Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J. Urol. 168(1), 9–12 (2002). https://​doi.​org/​S0022-5347(05)64820-3CrossRef
4.
Zurück zum Zitat J.L. Mohler, C.W. Gregory, O.H. Ford 3rd, D. Kim, C.M. Weaver, P. Petrusz, E.M. Wilson, F.S. French, The androgen axis in recurrent prostate cancer. Clin. Cancer Res. 10(2), 440–448 (2004)CrossRef J.L. Mohler, C.W. Gregory, O.H. Ford 3rd, D. Kim, C.M. Weaver, P. Petrusz, E.M. Wilson, F.S. French, The androgen axis in recurrent prostate cancer. Clin. Cancer Res. 10(2), 440–448 (2004)CrossRef
6.
Zurück zum Zitat C.D. Chen, D.S. Welsbie, C. Tran, S.H. Baek, R. Chen, R. Vessella, M.G. Rosenfeld, C.L. Sawyers, Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10(1), 33–39 (2004). https://doi.org/10.1038/nm972nm972 [pii]CrossRef C.D. Chen, D.S. Welsbie, C. Tran, S.H. Baek, R. Chen, R. Vessella, M.G. Rosenfeld, C.L. Sawyers, Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10(1), 33–39 (2004). https://​doi.​org/​10.​1038/​nm972nm972 [pii]CrossRef
8.
Zurück zum Zitat J. Veldscholte, C.A. Berrevoets, C. Ris-Stalpers, G.G. Kuiper, G. Jenster, J. Trapman, A.O. Brinkmann, E. Mulder, The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J. Steroid Biochem. Mol. Biol. 41(3-8), 665–669 (1992)CrossRef J. Veldscholte, C.A. Berrevoets, C. Ris-Stalpers, G.G. Kuiper, G. Jenster, J. Trapman, A.O. Brinkmann, E. Mulder, The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J. Steroid Biochem. Mol. Biol. 41(3-8), 665–669 (1992)CrossRef
9.
Zurück zum Zitat P.A. Watson, Y.F. Chen, M.D. Balbas, J. Wongvipat, N.D. Socci, A. Viale, K. Kim, C.L. Sawyers, Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc. Natl Acad. Sci. USA 107(39), 16759–16765 (2010). https://doi.org/10.1073/pnas.1012443107 CrossRefPubMed P.A. Watson, Y.F. Chen, M.D. Balbas, J. Wongvipat, N.D. Socci, A. Viale, K. Kim, C.L. Sawyers, Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc. Natl Acad. Sci. USA 107(39), 16759–16765 (2010). https://​doi.​org/​10.​1073/​pnas.​1012443107 CrossRefPubMed
11.
Zurück zum Zitat M.T. Schweizer, E.S. Antonarakis, H. Wang, A.S. Ajiboye, A. Spitz, H. Cao, J. Luo, M.C. Haffner, S. Yegnasubramanian, M.A. Carducci, M.A. Eisenberger, J.T. Isaacs, S.R. Denmeade, Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci. Transl. Med 7(269), 269ra262 (2015). https://doi.org/10.1126/scitranslmed.3010563 CrossRef M.T. Schweizer, E.S. Antonarakis, H. Wang, A.S. Ajiboye, A. Spitz, H. Cao, J. Luo, M.C. Haffner, S. Yegnasubramanian, M.A. Carducci, M.A. Eisenberger, J.T. Isaacs, S.R. Denmeade, Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci. Transl. Med 7(269), 269ra262 (2015). https://​doi.​org/​10.​1126/​scitranslmed.​3010563 CrossRef
13.
Zurück zum Zitat M.T. Schweizer, H. Wang, B. Luber, R. Nadal, A. Spitz, D.M. Rosen, H. Cao, E.S. Antonarakis, M.A. Eisenberger, M.A. Carducci, C. Paller, S.R. Denmeade, Bipolar androgen therapy for men with androgen ablation naive. Prostate Cancer.: Results Phase II BATMAN Study Prostate 76(13), 1218–1226 (2016). https://doi.org/10.1002/pros.23209 CrossRefPubMed M.T. Schweizer, H. Wang, B. Luber, R. Nadal, A. Spitz, D.M. Rosen, H. Cao, E.S. Antonarakis, M.A. Eisenberger, M.A. Carducci, C. Paller, S.R. Denmeade, Bipolar androgen therapy for men with androgen ablation naive. Prostate Cancer.: Results Phase II BATMAN Study Prostate 76(13), 1218–1226 (2016). https://​doi.​org/​10.​1002/​pros.​23209 CrossRefPubMed
15.
Zurück zum Zitat M. Kohli, Y. Ho, D.W. Hillman, J.L. Van Etten, C. Henzler, R. Yang, J.M. Sperger, Y. Li, E. Tseng, T. Hon, T. Clark, W. Tan, R.E. Carlson, L. Wang, H. Sicotte, H. Thai, R. Jimenez, H. Huang, P.T. Vedell, B.W. Eckloff, J.F. Quevedo, H.C. Pitot, B.A. Costello, J. Jen, E.D. Wieben, K.A.T. Silverstein, J.M. Lang, S.M. Dehm, Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance. Clin. Cancer Res. 23(16), 4704–4715 (2017). https://doi.org/10.1158/1078-0432.CCR-17-0017 CrossRefPubMedPubMedCentral M. Kohli, Y. Ho, D.W. Hillman, J.L. Van Etten, C. Henzler, R. Yang, J.M. Sperger, Y. Li, E. Tseng, T. Hon, T. Clark, W. Tan, R.E. Carlson, L. Wang, H. Sicotte, H. Thai, R. Jimenez, H. Huang, P.T. Vedell, B.W. Eckloff, J.F. Quevedo, H.C. Pitot, B.A. Costello, J. Jen, E.D. Wieben, K.A.T. Silverstein, J.M. Lang, S.M. Dehm, Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance. Clin. Cancer Res. 23(16), 4704–4715 (2017). https://​doi.​org/​10.​1158/​1078-0432.​CCR-17-0017 CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Y. Zhu, A. Sharp, C.M. Anderson, J.L. Silberstein, M. Taylor, C. Lu, P. Zhao, A.M. De Marzo, E.S. Antonarakis, M. Wang, X. Wu, Y. Luo, N. Su, D. Nava Rodrigues, I. Figueiredo, J. Welti, E. Park, X.J. Ma, I. Coleman, C. Morrissey, S.R. Plymate, P.S. Nelson, J.S. de Bono, J. Luo, Novel junction-specific and quantifiable in situ detection of AR-V7 and its clinical correlates in metastatic castration-resistant prostate cancer. Eur. Urol. 73(5), 727–735 (2018). https://doi.org/10.1016/j.eururo.2017.08.009 CrossRefPubMed Y. Zhu, A. Sharp, C.M. Anderson, J.L. Silberstein, M. Taylor, C. Lu, P. Zhao, A.M. De Marzo, E.S. Antonarakis, M. Wang, X. Wu, Y. Luo, N. Su, D. Nava Rodrigues, I. Figueiredo, J. Welti, E. Park, X.J. Ma, I. Coleman, C. Morrissey, S.R. Plymate, P.S. Nelson, J.S. de Bono, J. Luo, Novel junction-specific and quantifiable in situ detection of AR-V7 and its clinical correlates in metastatic castration-resistant prostate cancer. Eur. Urol. 73(5), 727–735 (2018). https://​doi.​org/​10.​1016/​j.​eururo.​2017.​08.​009 CrossRefPubMed
18.
Zurück zum Zitat C.A. Schneider, W.S. Rasband, K.W. Eliceiri, NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9(7), 671–675 (2012)CrossRef C.A. Schneider, W.S. Rasband, K.W. Eliceiri, NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9(7), 671–675 (2012)CrossRef
25.
Zurück zum Zitat P. Stattin, S. Lumme, L. Tenkanen, H. Alfthan, E. Jellum, G. Hallmans, S. Thoresen, T. Hakulinen, T. Luostarinen, M. Lehtinen, J. Dillner, U.H. Stenman, M. Hakama, High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. Int. J. Cancer 108(3), 418–424 (2004). https://doi.org/10.1002/ijc.11572 CrossRefPubMed P. Stattin, S. Lumme, L. Tenkanen, H. Alfthan, E. Jellum, G. Hallmans, S. Thoresen, T. Hakulinen, T. Luostarinen, M. Lehtinen, J. Dillner, U.H. Stenman, M. Hakama, High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. Int. J. Cancer 108(3), 418–424 (2004). https://​doi.​org/​10.​1002/​ijc.​11572 CrossRefPubMed
30.
Zurück zum Zitat A.R. Kristal, J.M. Schenk, Y. Song, K.B. Arnold, M.L. Neuhouser, P.J. Goodman, D.W. Lin, F.Z. Stanczyk, I.M. Thompson, Serum steroid and sex hormone-binding globulin concentrations and the risk of incident benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am. J. Epidemiol. 168(12), 1416–1424 (2008). https://doi.org/10.1093/aje/kwn272 CrossRefPubMedPubMedCentral A.R. Kristal, J.M. Schenk, Y. Song, K.B. Arnold, M.L. Neuhouser, P.J. Goodman, D.W. Lin, F.Z. Stanczyk, I.M. Thompson, Serum steroid and sex hormone-binding globulin concentrations and the risk of incident benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am. J. Epidemiol. 168(12), 1416–1424 (2008). https://​doi.​org/​10.​1093/​aje/​kwn272 CrossRefPubMedPubMedCentral
36.
Zurück zum Zitat X.B. Shi, A.H. Ma, L. Xia, H.J. Kung, R.W. de Vere White, Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res. 62(5), 1496–1502 (2002)PubMed X.B. Shi, A.H. Ma, L. Xia, H.J. Kung, R.W. de Vere White, Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res. 62(5), 1496–1502 (2002)PubMed
38.
39.
Zurück zum Zitat J. Tan, Y. Sharief, K.G. Hamil, C.W. Gregory, D.Y. Zang, M. Sar, P.H. Gumerlock, R.W. deVere White, T.G. Pretlow, S.E. Harris, E.M. Wilson, J.L.Mohler, F.S. French, Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol. Endocrinol. 11(4), 450–459 (1997). https://doi.org/10.1210/mend.11.4.9906 CrossRefPubMed J. Tan, Y. Sharief, K.G. Hamil, C.W. Gregory, D.Y. Zang, M. Sar, P.H. Gumerlock, R.W. deVere White, T.G. Pretlow, S.E. Harris, E.M. Wilson, J.L.Mohler, F.S. French, Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol. Endocrinol. 11(4), 450–459 (1997). https://​doi.​org/​10.​1210/​mend.​11.​4.​9906 CrossRefPubMed
42.
Zurück zum Zitat S.N. Mediwala, H. Sun, A.T. Szafran, S.M. Hartig, G. Sonpavde, T.G. Hayes, P. Thiagarajan, M.A. Mancini, M. Marcell, The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way. The Prostate 73(3), 267–277 (2013)CrossRef S.N. Mediwala, H. Sun, A.T. Szafran, S.M. Hartig, G. Sonpavde, T.G. Hayes, P. Thiagarajan, M.A. Mancini, M. Marcell, The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way. The Prostate 73(3), 267–277 (2013)CrossRef
Metadaten
Titel
Androgenic modulation of AR-Vs
verfasst von
Ana Caroline Hillebrand
Lolita Schneider Pizzolato
Gisele Branchini
Ilma Simoni Brum
Publikationsdatum
19.07.2018
Verlag
Springer US
Erschienen in
Endocrine / Ausgabe 2/2018
Print ISSN: 1355-008X
Elektronische ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-018-1682-5

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