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Loss of 14-3-3 in Prostate Cancer and Its Precursors

Departments of ¹ Pathology and Laboratory Medicine, ² Urology, ³ Pharmacology and Toxicology; the ⁴ Division of Biostatistics; and the ⁵ University of Indiana Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, and ⁶ MedImmune Inc., Gaithersburg, Maryland

Purpose: The 14-3-3 family proteins are highly conserved over many mammalian species. The isoform (also called HME-1 or stratifin) is expressed in epithelial cells. Loss of 14-3-3 is associated with failure to arrest the cell cycle at the G₂-M phase checkpoint after DNA damage that leads to increased G₂-type chromosomal aberrations. The role of 14-3-3 in prostatic carcinogenesis is uncertain.

Experimental Design: We studied one hundred and eleven specimens of invasive prostate adenocarcinoma with paired, adjacent high-grade prostatic intraepithelial neoplasia and normal prostate epithelium. Immunohistochemistry was used to detect the expression of 14-3-3. The findings were correlated with various clinical pathological parameters.

Results: 14-3-3 is ubiquitously expressed at high levels in normal prostate epithelium. Its expression is significantly decreased in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Ninety percent of samples of prostatic intraepithelial neoplasia had no or low 14-3-3 expression. Ninety-seven percent of invasive adenocarcinomas had no or low 14-3-3 expression. In most specimens (90%), suppression of 14-3-3 expression occurred during the development of prostatic intraepithelial neoplasia from normal epithelium.

Conclusions: Our data suggest that loss of 14-3-3 contributes to the development of prostate adenocarcinoma. 14-3-3 expression is significantly decreased during the progression of normal prostatic epithelium to prostatic intraepithelial neoplasia and invasive cancer.

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