Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion.
ABSTRACT NKX3.1 is a homeobox gene located at chromosome 8p21.2, and one copy is frequently deleted in prostate carcinoma. Prior studies of NKX3.1 mRNA and protein in human prostate cancer and prostatic intraepithelial neoplasia (PIN) have been conflicting, and expression in focal prostate atrophy lesions has not been investigated. Immunohistochemical staining for NKX3.1 on human tissue microarrays was decreased in most focal atrophy and PIN lesions. In carcinoma, staining was inversely correlated with Gleason grade. Fluorescence in situ hybridization showed that no cases of atrophy had loss or gain of 8p, 8 centromere, or 8q24 (C-MYC) and only 12% of high-grade PIN lesions harbored loss of 8p. By contrast, NKX3.1 staining in carcinoma was correlated with 8p loss and allelic loss was inversely related to Gleason pattern. Quantitative reverse transcription-PCR for NKX3.1 mRNA using microdissected atrophy revealed a concordance with protein in five of seven cases. In carcinoma, mRNA levels were decreased in 6 of 12 cases but mRNA levels correlated with protein levels in only 4 of 12 cases, indicating translational or post-translational control. In summary, NKX3.1 protein is reduced in focal atrophy and PIN but is not related to 8p allelic loss in these lesions. Therefore, whereas genetic disruption of NKX3.1 in mice leads to PIN, nongenetic mechanisms reduce NKX3.1 protein levels early in human prostate carcinogenesis, which may facilitate both proliferation and DNA damage in atrophic and PIN cells. Monoallelic deletions on chromosome 8p are associated with more advanced invasive and aggressive disease.
Article: Prostatic preneoplasia and beyond.[show abstract] [hide abstract]
ABSTRACT: Prostate cancer is a heterogeneous neoplasm both with regard to its development, molecular abnormalities and clinical course. For example, in the United States, 1 in 6 men is diagnosed with prostate cancer whilst only 1 in 34 dies of metastatic disease [A. Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, M.J. Thun, Cancer Statistics, 2007, CA Cancer J. Clin. 57 (2007) 43-66]. In this review, we summarise novel understandings of the early molecular events in prostatic carcinogenesis that may underlie both the molecular and clinical heterogeneity. Issues covered include those related to stem cells and embryonic signalling, oncogene/tumor suppressor abnormalities, androgen signalling, apoptosis and the nature of tumor-stromal interactions. Emphasis is placed on signalling pathway abnormalities, their causation, consequences and interactions. For example, genomic abnormalities involving the TMPRSS2-ETS and PTEN loci and the resulting signalling effects suggest the importance of genomic instability as a crucial factor in the emergence of this neoplasm. Together with new insights into signalling pathways consequent to abnormalities such as these, a greater understanding of the pathophysiology involved in prostatic carcinogenesis will lead to targeted approaches for both therapy and chemoprevention in the future.Biochimica et Biophysica Acta 05/2008; 1785(2):156-81. · 4.66 Impact Factor