No abstract

A major obstacle in treating prostate cancer is the development of androgen-independent disease. In this study, we examined LEF1 expression in androgen-independent cancer as well as its regulation of androgen receptor (AR) expression, prostate cancer growth, and invasion in androgenindependent prostate cancer cells. Affymetrix microarray analysis of LNCaP and LNCaP-AI (androgen-independent variant LNCaP) cells revealed 100-fold increases in LEF1 expression in LNCaP-AI cells. We showed that LEF1 overexpression in LNCaP cells resulted in increased AR expression and consequently enhanced growth and invasion ability, whereas LEF1 knockdown in LNCaP-AI cells decreased AR expression and, subsequently, growth and invasion capacity. Chromatin immunoprecipitation, gel shift, and luciferase assays confirmed LEF1 occupancy and regulation of the AR promoter. Thus, we identified LEF1 as a potential marker for androgen-independent disease and as a key regulator of AR expression and prostate cancer growth and invasion. LEF1 is highly expressed in androgen-independent prostate cancer, potentially serving as a marker for androgen-independent disease. [Cancer Res 2009;69(8):3332-8] IntroductionA variety of theories have been proposed regarding the mechanism by which prostate cancer cells progress to aggressive phenotypes, including increased invasive and metastatic potentials, and developing resistance to androgen ablation therapy (1-3). Of great importance, increasing evidence fortify that increased androgen receptor (AR) expression and altered AR function, due to amplification, overexpression and mutation, play a dominant role in the progression and treatment failure of advanced prostate cancer (4-8). The role of AR in the invasive and metastatic potential of prostate cancer is suggested by several studies (9-11), including a recent study by Hara and colleagues (12). However, the direct role that AR plays in the invasion and metastasis of prostate cancer remains understudied.Regulation of AR expression is complex, involving positive (13, 14) and negative (15) control by transcription factors. AR expression is also linked to cross-talk with growth factor receptor or other signaling pathways (16-24). LEF1, lymphoid enhancerbinding factor 1 in the Wnt signaling pathway, has been indicated to regulate AR expression (25). LEF1/TCF is the nuclear transducer on activated the Wnt pathway. Members of the family represent a group of proteins with DNA-binding activities that specifically recognize and bind to a contiguous six-base consensus sequence, 5 ¶-a/ta/t-C-A-A-G-3 ¶ within the 5 ¶ promoter regions of Wnt target genes (26). There are eight putative LEF1 binding sites described at the AR promoter region regulating its expression (25).In addition to its function in a variety of developmental processes including stem cell renewal, embryonic development, and tissue differentiation, more recent evidence indicates that aberrant activity of the Wnt signaling pathway is involved in the tumorigenesis of several organ systems incl...