Nature Medicine
6, 703 - 706 (2000)
doi:10.1038/76287
Glucocorticoids can promote androgen-independent growth of prostate cancer
cells through a mutated androgen receptorXiao-Yan Zhao1, Peter J. Malloy1, Aruna V. Krishnan1, Srilatha Swami1, Nora M. Navone2, Donna M. Peehl3
& David Feldman11
Department of Medicine, Stanford University School
of Medicine, Stanford, California 94305,
USA
2
Department of Genito-Urinary Medical Oncology, University
of Texas M.D. Anderson Cancer Center, Houston, Texas
77030, USA
3
Department of Urology, Stanford University School of
Medicine, Stanford, California 94305,
USA
Correspondence should be addressed to David Feldman feldman@cmgm.stanford.eduThe androgen receptor (AR) is involved in the development, growth and progression
of prostate cancer1 (CaP). CaP often progresses from an androgen-dependent
to an androgen-independent tumor, making androgen ablation therapy ineffective.
However, the mechanisms for the development of androgen-independent CaP are
unclear. More than 80% of clinically androgen-independent prostate tumors
show high levels of AR expression1. In some CaPs, AR levels
are increased because of gene amplification2 and/or overexpression,
whereas in others, the AR is mutated3,
4,
5. Nonetheless, the
involvement of the AR in the transition of CaP to androgen-independent growth
and the subsequent failure of endocrine therapy are not fully understood.
Here we show that in CaP cells from a patient who failed androgen ablation
therapy, a doubly mutated AR functioned as a high-affinity cortisol/cortisone
receptor (ARccr). Cortisol, the main circulating glucocorticoid,
and its metabolite, cortisone, both equally stimulate the growth of these
CaP cells and increase the secretion of prostate-specific antigen in the absence
of androgens. The physiological concentrations of free cortisol and total
cortisone in men6,
7 greatly exceed the binding affinity of
the ARccr and would activate the receptor, promoting CaP cell
proliferation. Our data demonstrate a previously unknown mechanism for the
androgen-independent growth of advanced CaP. Understanding this mechanism
and recognizing the presence of glucocorticoid-responsive AR mutants are important
for the development of new forms of therapy for the treatment of this subset
of CaP.
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