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Am J Pathol. 2018 Jan;188(1):216-228. doi: 10.1016/j.ajpath.2017.08.036. Epub 2017 Nov 7.

Antiandrogens Reduce Intratumoral Androgen Concentrations and Induce Androgen Receptor Expression in Castration-Resistant Prostate Cancer Xenografts.

Author information

1
Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
2
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
3
Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland; R&D Oncology Research, Orion Pharma, Turku, Finland.
4
School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
5
R&D Oncology Research, Orion Pharma, Turku, Finland.
6
Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland; Department of Mathematics and Statistics, University of Turku, Turku, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
7
Center for Bone and Arthritis Research, The Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
8
ANZAC Research Institute, University of Sydney, Concord, New South Wales, Australia.
9
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; Department of Mathematics and Statistics, University of Turku, Turku, Finland.
10
Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland; Functional Foods Forum, University of Turku, Turku, Finland.
11
Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland; Center for Bone and Arthritis Research, The Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden. Electronic address: matti.poutanen@utu.fi.

Abstract

The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that, similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Herein, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P < 0.01) intratumoral testosterone and dihydrotestosterone concentrations in the CR-VCaP tumors, indicating that the reduction in intratumoral androgens is a novel mechanism by which antiandrogens mediate their effects in CRPC. Antiandrogen treatment also altered the expression of multiple enzymes potentially involved in steroid metabolism. Identical to clinical CRPC, the expression levels of the full-length AR (twofold, P < 0.05) and the AR splice variants 1 (threefold, P < 0.05) and 7 (threefold, P < 0.01) were further increased in the antiandrogen-treated tumors. Nonsignificant effects were observed in the expression of certain classic androgen-regulated genes, such as TMPRSS2 and KLK3, despite the low levels of testosterone and dihydrotestosterone. However, other genes recently identified to be highly sensitive to androgen-regulated AR action, such as NOV and ST6GalNAc1, were markedly altered, which indicated reduced androgen action. Taken together, the data indicate that, besides blocking AR, antiandrogens modify androgen signaling in CR-VCaP xenografts at multiple levels.

PMID:
29126837
DOI:
10.1016/j.ajpath.2017.08.036
[Indexed for MEDLINE]

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