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Cited by 433

The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.

Intratumoral De Novo Steroid Synthesis Activates Androgen Receptor in Castration-Resistant Prostate Cancer and Is Upregulated by Treatment with CYP17A1 Inhibitors

Open access
Cai, Changmeng, Chen, Sen, Ng, Patrick, Bubley, Glenn J., Nelson, Peter S., Mostaghel, Elahe A., Marck, Brett, Matsumoto, Alvin M., Simon, Nicholas I., Wang, Hongyun, Chen, Shaoyong, Balk, Steven P.·2011·Cancer Research
DOI 10.1158/0008-5472.can-11-0532
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Abstract

Relapse of castration-resistant prostate cancer (CRPC) that occurs after androgen deprivation therapy of primary prostate cancer can be mediated by reactivation of the androgen receptor (AR). One important mechanism mediating this AR reactivation is intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone. DHEA and androstenedione are synthesized by the adrenals through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1, so that CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, the significance of intratumoral CYP17A1 and de novo androgen synthesis from cholesterol in CRPC, and the mechanisms contributing to CYP17A1 inhibitor resistance/relapse, remain to be determined. We report that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografts imposes selective pressure for increased intratumoral expression of CYP17A1, thereby generating a mechanism for development of resistance to CYP17A1 inhibitors. Supporting the clinical relevance of this mechanism, we found that intratumoral expression of CYP17A1 was markedly increased in tumor biopsies from CRPC patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a progesterone responsive T877A mutant AR are not CYP17A1 dependent, but that AR activity in these cells is still steroid dependent and mediated by upstream CYP11A1-dependent intraturmoral pregnenolone/progesterone synthesis. Together, our results indicate that CRPCs resistant to CYP17A1 inhibition may remain steroid dependent and therefore responsive to therapies that can further suppress de novo intratumoral steroid synthesis. Cancer Res; 71(20); 6503–13. ©2011 AACR.

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Metadata

Authors
Cai, C., Chen, S., Ng, P., Bubley, G. J., Nelson, P. S., Mostaghel, E. A., Marck, B., Matsumoto, A. M., Simon, N. I., Wang, H., Chen, S., & Balk, S. P.
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2011-10-12
Volume
71
Issue
20
Pages
6503-6513
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-11-0532
OpenAlex
W2147166694
Cited by
433
References
12
FWCI
36.37
Type
journal article
Language
en
Open access
bronze

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CoChat. (2026). Citation check: Intratumoral De Novo Steroid Synthesis Activates Androgen Receptor in Castration-Resistant Prostate Cancer and Is Upregulated by Treatment with CYP17A1 Inhibitors. https://app.cochat.ai/papers/10.1158/0008-5472.can-11-0532
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Cai, C., Chen, S., Ng, P., Bubley, G. J., Nelson, P. S., Mostaghel, E. A., Marck, B., Matsumoto, A. M., Simon, N. I., Wang, H., Chen, S., & Balk, S. P. (2011). Intratumoral De Novo Steroid Synthesis Activates Androgen Receptor in Castration-Resistant Prostate Cancer and Is Upregulated by Treatment with CYP17A1 Inhibitors. Cancer Research. https://doi.org/10.1158/0008-5472.can-11-0532

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