TY - JOUR
T1 - 14-3-3η amplifies androgen receptor actions in prostate cancer
AU - Titus, Mark A.
AU - Tan, Jiann An
AU - Gregory, Christopher W.
AU - Ford, O. Harris
AU - Subramanian, Romesh R.
AU - Fu, Haian
AU - Wilson, Elizabeth M.
AU - Mohler, James L.
AU - French, Frank S.
PY - 2009/12/15
Y1 - 2009/12/15
N2 - Purpose: Androgen receptor abundance and androgen receptor-regulated gene expression in castration-recurrent prostate cancer are indicative of androgen receptor activation in the absence of testicular androgen. Androgen receptor transactivation of target genes in castration-recurrent prostate cancer occurs in part through mitogen signaling that amplifies the actions of androgen receptor and its coregulators. Herein we report on the role of 14-3-3η in androgen receptor action. Experimental Design and Results: Androgen receptor and 14-3-3η colocalized in COS cell nuclei with and without androgen, and 14-3-3η promoted androgen receptor nuclear localization in the absence of androgen. 14-3-3η interacted with androgen receptor in cell-free binding and coimmunoprecipitation assays. In the recurrent human prostate cancer cell line, CWR-R1, native endogenous androgen receptor transcriptional activation was stimulated by 14-3-3η at low dihydrotestosterone concentrations and was increased by epidermal growth factor. Moreover, the dihydrotestosterone- and epidermal growth factor-dependent increase in androgen receptor transactivation was inhibited by a dominant negative 14-3-3η. In the CWR22 prostate cancer xenograft model, 14-3-3η expression was increased by androgen, suggesting a feed-forward mechanism that potentiates both 14-3-3η and androgen receptor actions. 14-3-3η mRNA and protein decreased following castration of tumor-bearing mice and increased in tumors of castrate mice after treatment with testosterone. CWR22 tumors that recurred 5 months after castration contained 14-3-3η levels similar to the androgenstimulated tumors removed before castration. In a human prostate tissue microarray of clinical specimens, 14-3-3η localized with androgen receptor in nuclei, and the similar amounts expressed in castration-recurrent prostate cancer, androgen-stimulated prostate cancer, and benign prostatic hyperplasia were consistent with androgen receptor activation in recurrent prostate cancer. Conclusion: 14-3-3η enhances androgen- and mitogen-induced androgen receptor transcriptional activity in castration-recurrent prostate cancer.
AB - Purpose: Androgen receptor abundance and androgen receptor-regulated gene expression in castration-recurrent prostate cancer are indicative of androgen receptor activation in the absence of testicular androgen. Androgen receptor transactivation of target genes in castration-recurrent prostate cancer occurs in part through mitogen signaling that amplifies the actions of androgen receptor and its coregulators. Herein we report on the role of 14-3-3η in androgen receptor action. Experimental Design and Results: Androgen receptor and 14-3-3η colocalized in COS cell nuclei with and without androgen, and 14-3-3η promoted androgen receptor nuclear localization in the absence of androgen. 14-3-3η interacted with androgen receptor in cell-free binding and coimmunoprecipitation assays. In the recurrent human prostate cancer cell line, CWR-R1, native endogenous androgen receptor transcriptional activation was stimulated by 14-3-3η at low dihydrotestosterone concentrations and was increased by epidermal growth factor. Moreover, the dihydrotestosterone- and epidermal growth factor-dependent increase in androgen receptor transactivation was inhibited by a dominant negative 14-3-3η. In the CWR22 prostate cancer xenograft model, 14-3-3η expression was increased by androgen, suggesting a feed-forward mechanism that potentiates both 14-3-3η and androgen receptor actions. 14-3-3η mRNA and protein decreased following castration of tumor-bearing mice and increased in tumors of castrate mice after treatment with testosterone. CWR22 tumors that recurred 5 months after castration contained 14-3-3η levels similar to the androgenstimulated tumors removed before castration. In a human prostate tissue microarray of clinical specimens, 14-3-3η localized with androgen receptor in nuclei, and the similar amounts expressed in castration-recurrent prostate cancer, androgen-stimulated prostate cancer, and benign prostatic hyperplasia were consistent with androgen receptor activation in recurrent prostate cancer. Conclusion: 14-3-3η enhances androgen- and mitogen-induced androgen receptor transcriptional activity in castration-recurrent prostate cancer.
UR - http://www.scopus.com/inward/record.url?scp=73349110927&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73349110927&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-08-1976
DO - 10.1158/1078-0432.CCR-08-1976
M3 - Article
C2 - 19996220
AN - SCOPUS:73349110927
SN - 1078-0432
VL - 15
SP - 7571
EP - 7581
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -