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Tissue Levels of Androgens in Castration-Recurrent Prostate Cancer

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Androgen Action in Prostate Cancer

Abstract

AR remains active in growth signaling despite castrate levels of circulating androgens. AR protein and AR-regulated proteins are expressed in CaP that recurs during ADT in both the primary and bone metastases. AR activation in recurrent CaP may occur by a variety of mechanisms that alter the sensitivity or specificity of AR. Recent studies using androgen-independent CaP cell lines and xenografts demonstrated that AR over-expression allowed recurrent CaP growth in the presence of castrate levels of circulating androgens. However, AR mutations that prevented ligand-binding prevented recurrent growth; over-expressed AR required ligand to confer recurrent growth. We showed that DHT levels were decreased by 91% in clinical specimens of castration-recurrent CaP (1.25 pmol/gm tissue) compared to androgen-stimulated benign prostate and DHT levels were sufficient for AR activation in most specimens of recurrent CaP. Other investigators have supported these findings in prostatectomy specimens obtained after 3-6 months of ADT and benign prostate specimens after 1 month of ADT. Perturbations in androgen metabolism pathways during ADT may allow intracrine production of DHT from adrenal androgens and even cholesterol. The tissue levels of T and DHT support a new paradigm. CaP that recurs after medical or surgical castration is not “androgen-independent” because recurrent CaP usually has androgen levels sufficient to activate AR. New treatments should be directed at preventing intracrine synthesis of testicular androgens from adrenal androgens or cholesterol, degrading these androgens or, failing both, destroying AR.

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  1. Department of Urologic Oncology, , Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA

    James L. Mohler

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  1. James L. Mohler
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  2. Mark A. Titus
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Correspondence to James L. Mohler .

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James Mohler Donald Tindall

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Mohler, J.L., Titus, M.A. (2009). Tissue Levels of Androgens in Castration-Recurrent Prostate Cancer. In: Mohler, J., Tindall, D. (eds) Androgen Action in Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69179-4_23

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