title: Human ASH1 expression in prostate cancer with neuroendocrine differentiation.
abstract: Neuroendocrine differentiation in prostate cancer correlates with overall prognosis and disease progression after androgen-deprivation therapy, although its specific mechanisms are currently poorly understood. A role of Notch pathway has been reported in determining neuroendocrine phenotype of normal and neoplastic tissues. The aim of this study was to analyze whether this pathway might affect neuroendocrine differentiation in prostate cancer. Human achaete-scute homolog 1 (hASH1), a pivotal member of the Notch pathway, was investigated in 80 prostate cancers selected and grouped according to chromogranin A immunohistochemistry, as follows: prostate cancers without neuroendocrine differentiation, untreated (25 cases); prostate cancers with neuroendocrine differentiation, untreated (40 cases); prostate cancers with previous androgen-deprivation therapy, all having neuroendocrine differentiation (15 cases). Human ASH1 protein was analyzed by immunohistochemistry, whereas the presence of hASH1 mRNA transcripts was investigated on paraffin material by real-time PCR. By immunohistochemistry, hASH1 was colocalized with chromogranin A in neuroendocrine cells of normal prostatic gland. It was absent in all but one prostate cancers without neuroendocrine differentiation, whereas it was positive in 25% of prostate cancers with neuroendocrine differentiation/untreated, with a significant correlation with the extent of neuroendocrine features (P=0.02). Moreover, comparing untreated and treated prostate cancers with neuroendocrine differentiation, a positive association with androgen-deprivation therapy was observed (P=0.01). In prostate cancers with neuroendocrine differentiation, RNA analysis confirmed the association of higher transcript levels in androgen deprivation-treated compared with untreated patients (P=0.01). In addition, hASH1 mRNA analysis in microdissected chromogranin A-positive and chromogranin A-negative areas within the same tumor demonstrated a two- to sevenfold increase of hASH1 mRNA expression in chromogranin A-positive tumor cell populations.
authors.affiliation: Division of Pathology, Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Turin, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Rapa
authors.forename: Paolo
authors.initials: P
authors.lastname: Ceppi
authors.forename: Enrico
authors.initials: E
authors.lastname: Bollito
authors.forename: Rosj
authors.initials: R
authors.lastname: Rosas
authors.forename: Susanna
authors.initials: S
authors.lastname: Cappia
authors.forename: Elisa
authors.initials: E
authors.lastname: Bacillo
authors.forename: Francesco
authors.initials: F
authors.lastname: Porpiglia
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053379:Chromogranin A / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D053379:Chromogranin A; D012333:RNA, Messenger; C065500:ASCL1 protein, human