Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Jul 15;72(14):3457-62.
doi: 10.1158/0008-5472.CAN-11-3892. Epub 2012 Jun 18.

Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer

Rong Hu  1 , Changxue Lu, Elahe A Mostaghel, Srinivasan Yegnasubramanian, Meltem Gurel, Clare Tannahill, Joanne Edwards, William B Isaacs, Peter S Nelson, Eric Bluemn, Stephen R Plymate, Jun Luo
Affiliations

Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer

Rong Hu et al. Cancer Res. .

Abstract

Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of androgen receptor signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splice variants (AR-Vs) lack the androgen receptor ligand-binding domain (AR-LBD), the intended _target of androgen deprivation therapies including CRPC therapies such as abiraterone and MDV3100. While the canonical full-length androgen receptor (AR-FL) and AR-Vs are both increased in CRPCs, their expression regulation, associated transcriptional programs, and functional relationships have not been dissected. In this study, we show that suppression of ligand-mediated AR-FL signaling by _targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPCs. Importantly, treatment-induced AR-Vs activated a distinct expression signature enriched for cell-cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppressed the AR-Vs signature and activated expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 or abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, paralleled increased expression of the androgen receptor-driven cell-cycle gene UBE2C. Expression of AR-V7, but not AR-FL, was positively correlated with UBE2C in clinical CRPC specimens. Together, our findings support an adaptive shift toward AR-V-mediated signaling in a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapy.

PubMed Disclaimer

Conflict of interest statement

There are no conflicts to disclose

Figures

Figure 1
Figure 1
Regulation of AR-V expression by AR-FL signaling in LNCaP95 and VCaP cells. A: Increased AR-Vs following suppression of AR-FL by ligand depletion (R1881-), siRNA _targeting AR-LBD (AR-LBD siRNA), or MDV3100 (10μM). Protein levels of AR (by the N20 antibody that detects both AR-FL and AR-Vs), AR-V7, PSA, ERG, and beta-actin were assessed by Western blot. B: Immunofluorescent images showing decreased or loss of AR-V7 nuclear staining in the presence of 1nM R1881.
Figure 2
Figure 2
Distinctive expression patterns of gene sets representing the core transcriptional output of AR-V7 and AR-FL. A. Expression of the “AR-V7 UP” and “AR-FL UP” gene sets in parental LNCaP cells transiently transfetced with AR-V7 in the presence (R1881) or absence (CSS) of AR-FL signaling. B. Expression of the “AR-V7 UP” gene set in stable clones of LNCaP cells with (AR-FL+) or without (AR-FL−) endogenous AR-FL following transient transfection with either AR-V7 or ARV567ES. Each experiment was repeated 3 times. C. Expression profiles of the “AR-FL UP” and “AR-V7 UP” gene sets in LNCaP95 cells following suppression of AR-FL only (AR-LBD siRNA), or both AR-FL and AR-Vs (AR-DBD siRNA), in the presence or absence of 1nM R1881.
Figure 3
Figure 3
Increased expression of UBE2C parallels that of AR-Vs following treatment with MDV3100 and abiraterone. A. Increased AR-V7 and UBE2C expression following MDV3100 treatment in the presence of 1nM R1881 in LNCaP95 cells. B. Correlation of UBE2C and AR (AR-V7, ARV567ES, and AR-FL) expression in LuCaP35CR xenografts treated with control vehicles. C. Correlation of UBE2C and AR (AR-V7, ARV567ES, and AR-FL) expression in LuCaP35CR xenografts treated with abiraterone.
Figure 4
Figure 4
Tissue microarray analysis of correlation between AR (AR-FL and AR-7) and UBE2C in castration-resistant prostate specimens (n=67). A. Representative high power TMA images showing nuclear staining for AR-FL, AR-V7, and UBE2C. B. No correlation between AR-FL and UBE2C (r=0.01, p>0.05) in 67 CRPC specimens. C. Significant correlation between AR-V7 and UBE2C (r=0.41, p<0.05) in 67 CRPC specimens.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Attard G, Cooper CS, de Bono JS. Steroid hormone receptors in prostate cancer: a hard habit to break? Cancer Cell. 2009;16:458–62. - PubMed
    1. Mostaghel EA, Nelson PS. Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin Endocrinol Metab. 2008;22:243–58. - PMC - PubMed
    1. Cai C, Chen S, Ng P, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 2011;71:6503–13. - PMC - PubMed
    1. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90. - PMC - PubMed
    1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005. - PMC - PubMed

Publication types

MeSH terms

  NODES
Project 1
twitter 2