Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer

Purpose: NKX3.1, a member of the family of homeobox genes, exhibits prostat e tissue specific expression and appears to play a role in mouse prostate d evelopment. Rapid induction of NKX3.1 gene expression in response to androg ens has also been described. On the basis of the established role of androg ens in prostatic growth and differentiation and studies showing an associat ion of aberrant homeobox gene expression with the neoplastic process, we hy pothesize that alterations of NKX3.1 gene expression play a role in prostat e tumorigenesis. Materials and Methods: NKX3.1 expression was analyzed in matched, microdiss ected normal and tumor tissues from 52 primary prostate cancer specimens fr om radical prostatectomy by semiquantitative RT-PCR and in situ hybridizati on and correlated with the clinicopathologic features. NKX3.1 expression wa s quantified as differential expression between matched tumor and normal ti ssues and was grouped as overexpression in tumor tissue, reduced expression in tumor tissue and no change between tumor and normal tissues. Androgen r egulation of NKX3.1 expression was also studied in LNCaP cells. Androgen re ceptor (AR) expression in prostate tumor and normal tissue was correlated w ith NKX3. I expression. Results: Comparison of NKX3.1 expression between normal and tumor tissues r evealed overexpression in 31% tumor specimens (16 of 52), decreased express ion in 21% tumor specimens (11 of 52) and no change in 48% specimens (25 of 52). When these expression patterns were stratified by organ confined and non-organ-confined tumor, a higher percentage of patients exhibited NKX3, I overexpression in non-organ confined tumor (40%) versus organ confined tum or (22%). Elevated NKX3.1 expression significantly correlated with tumor vo lume and serum prostate specific antigen (PSA) level in the NKX3.1 overexpr ession group (p <0.05). Metastatic prostate cancer cell lines did not exhib it mutations in the protein coding sequence of NKX3.1. Additionally, the NK X3. I expression correlated with AR expression (p <0.01) in vivo in human p rostate tissues. Comparison of PSA and NKX3.1 expression in response to and rogen revealed a rapid androgen mediated induction of NKX3.1 expression in LNCaP cells. In situ hybridization analysis of representative specimens con firmed RT-PCR observations. Conclusions: These results suggest an association of NKX3.1 with a more agg ressive phenotype of carcinoma of the prostate. Correlation of AR expressio n with NKX3.1 in human prostate tissues underscores the androgen regulation of NKX3.1 in the physiologic context of human prostate tissues.