Constitutively active splice variants of the androgen receptor (AR) are frequently expressed (59% of metastases) following castration in prostate cancer patients and are associated with earlier tumor recurrence compared to tumors containing only wild-type (wt) AR. In most tumors the variant is expressed along with wt-AR. When wtAR and variant AR are expressed in cells following castration there is a marked decrease in IGF type 1 receptor expression (IGF-IR), an AR target whose expression is increased by wtAR. In order to understand these findings we expressed the AR splice variant in which exons 5, 6, and 7 are skipped during AR splicing resulting in constitutively active ARv567es along with wtAR in a prostate cancer cell line not expressing AR, M12, as well as ARv567es in AR positive LnCaP cells. In both lines ARv567es was found only in the nucleus in the absence of ligand but wtAR had also been transported to the nucleus and absolute levels of AR protein were increased in the absence of ligand in cells expressing the variant. The increase in wtAR protein is due to decreased degradation of wtAR associated with ARv567es. When ligand was added, PSA response was increased 5-fold over cells transfected only with wtAR. Further, whereas transfection with wtAR enhances IGF-IR expression and response to IGF-I ligand, in the presence of ARv567es IGF-IR expression in response to IGF-I was suppressed. When ARv567es was HA tagged and expressed along with wtAR pull-down of ARv567es with HA resulted in concomitant precipitation of wtAR. Subsequent deletion analysis of ARv567es demonstrated direct binding between the two ARs in specific cystine-rich domains. Further, wtAR-induced IGF-IR expression is a non-genomic AR cytoplasmic action through binding to src and MAPK phosphorylation. Although ARv567es binds src, phosphorylation of MAPK does not occur. Finally, when LnCaP cells expressing ARv567es were grown sc with MatrigelTM in immuno-compromised mice there was no response to castration as opposed to slowed growth of LnCaP controls. These data indicate that the presence of the castration-induced ARv567es not only effects progression of prostate cancer by its own constitutive activity but also changes the function of the wt or full-length AR and provides an additional mechanism for AR-induced prostate cancer progression following castration.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 631.