Androgen receptor mutation (T877A) promotes prostate cancer cell growth and cell survival

• Published in: Oncogene Vol. 25; no. 28; pp. 3905 - 3913
• Main Authors: Sun, C, Shi, Y, Xu, L L, Nageswararao, C, Davis, L D, Segawa, T, Dobi, A, McLeod, D G, Srivastava, S
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 29.06.2006
• Subjects: Androgen receptors; Androgens; Apoptosis; Apoptosis - genetics; Cell Division - genetics; Cell growth; Cell Line, Tumor; Cell survival; Cell Survival - genetics; Gene expression; Genes, p53; Genetic Vectors; Humans; Male; Mutation; Oncology; p53 Protein; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Receptors, Androgen - genetics; Receptors, Androgen - physiology; Regulatory proteins; Transcriptional Activation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209424

Alteration of the AR functions due to amplification, overexpression and somatic mutation of the AR itself or altered interaction of AR with other cell growth regulatory proteins, may contribute to a significant subset of advanced prostate cancer (CaP). Very little is known about the pathways impacted by AR dysfunctions, although CaP associated AR alterations suggest the biological role of the AR dysfunction in disease progression. Comparative evaluations of wild type (wt) AR and mutant (mt) ARs in appropriate experimental models should provide a better understanding of the functional impact of AR alterations in CaP. Here, we provide direct evidence showing cell growth/cell survival promoting effects of the widely studied CaP associated AR mutation (T877A). In contrast to Ad-wtAR or Ad-control infected LNCaP or LAPC4 cells, Ad-mtAR (T877A) infected LNCaP or LAPC4 cells continued to grow in the androgen-deprived medium and exhibited an androgen independent AR-transcription factor activity. Further, Ad-mtAR (T877A) infected LNCaP or LAPC4 cells exhibited enhanced cell growth in the presence of lower concentrations of the synthetic androgen, R1881. Of note, Ad-mtAR (T877A) infected LNCaP cells showed striking resistance to cell growth inhibition/apoptosis mediated by the wt p53. Taken together, these findings provide novel insights into the AR dysfunctions resulting from the T877A mutation and functionally similar AR alterations may provide selective cell growth/survival advantage for CaP progression. These observations have important implications for developing biology-based prognostic biomarkers and therapeutic strategies for CaP showing such AR dysfunctions.