Identification of novel subsets of high grade prostate intraepithelial neoplasia [HGPIN] and analysis of the distribution of suppressor of fused [SuFu] during the cell cycle

High grade prostate intraepithelial neoplasia [HGPIN] is thought to be the precursor lesion to prostate cancer. The use of extended core biopsy series has decreased the correlation of finding HGPIN on biopsy and diagnosis of cancer on rebiopsy. Currently, there is no clinical mechanism to determine which HGPIN lesions will progress to cancer. In this study we hypothesized that there are differences in protein expression that will allow us to identify subsets of HGPIN lesions. We have identified two distinct subsets of HGPIN through the observation of differential expression of four immunohistochemical markers: acetylated alpha-tubulin [AcT], Ki-67, Gli2 and vascular endothelial growth factor [VEGF]. Importantly, the HGPIN subsets could not be distinguished by current standard histopathological parameters. Further studies are needed to determine the role of these novel subsets in the progression of HGPIN to cancer.;One of the least understood features of the cell cycle is the formation and enrichment of proteins at the midbody, also known as the intracellular bridge. Depletion of midbody localized proteins results in defective midbody formation and/or cytokinesis. Suppressor of Fused [SuFu], a member of the Hedgehog [Hh] pathway is a significant target of current research due to its function as a negative regulator of the Hh signaling pathway. While SuFu is emerging as the dominant negative regulator of the Hh pathway, its role in the etiology of disease is only beginning to be understood. SuFu is known to localize to the primary cilium, cytoplasm and nucleus, and interacts with numerous proteins within the hedgehog pathway including the Gli transcription factors. We have identified a consistent pattern of enrichment of SuFu at the midbody of cultured human prostate epithelial cells. We have also identified other cell lines which demonstrate both positive and negative expression patterns of SuFu at the midbody. SiRNA mediated knockdown of SuFu in prostate and brain cancer cells resulted in a significant increase in proliferation as determined by increased Ki67 expression. We postulate that the novel finding of SuFu in the midbody may represent a unique function of SuFu that is independent of its known function within the Hh pathway.