title: Amplification and overexpression of vinculin are associated with increased tumour cell proliferation and progression in advanced prostate cancer.
abstract: Androgen withdrawal is the standard treatment for advanced prostate cancer. Although this therapy is initially effective, nearly all prostate cancers become refractory to it. Approximately 15% of these castration-resistant prostate cancers harbour a genomic amplification at 10q22. The aim of this study was to explore the structure of the 10q22 amplicon and to determine the major driving genes. Application of high-resolution array-CGH using the 244k Agilent microarrays to cell lines with 10q22 amplification allowed us to narrow down the common amplified region to a region of 5.8 megabases. We silenced each of the genes of this region by an RNAi screen in the prostate cancer cell lines PC-3 and 22Rv1. We selected genes with a significant growth reduction in the 10q22 amplified cell line PC-3, but not in the non-amplified 22Rv1 cells, as putative target genes of this amplicon. Immunohistochemical analysis of the protein expression of these candidate genes on a tissue microarray enriched for 10q22 amplified prostate cancers revealed vinculin as the most promising target of this amplicon. We found a strong association between vinculin gene amplification and overexpression (p < 0.001). Further analysis of 443 specimens from across all stages of prostate cancer progression showed that vinculin expression was highest in castration-resistant prostate cancers, but negative or very low in benign prostatic hyperplasia (p < 0.0001). Additionally, high tumour cell proliferation measured by Ki67 expression was significantly associated with high vinculin expression in prostate cancer (p < 0.0001). Our data suggest that vinculin is a major driving gene of the 10q22 amplification in prostate cancer and that vinculin overexpression might contribute to prostate cancer progression by enhancing tumour cell proliferation.
authors.affiliation: Institute for Pathology, University Hospital Basel, Basel, Switzerland. christian.ruiz@unibas.ch
authors.forename: Christian
authors.initials: C
authors.lastname: Ruiz
authors.forename: David R
authors.initials: DR
authors.lastname: Holz
authors.forename: Martin
authors.initials: M
authors.lastname: Oeggerli
authors.forename: Sandra
authors.initials: S
authors.lastname: Schneider
authors.forename: Irma M
authors.initials: IM
authors.lastname: Gonzales
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Kiefer
authors.forename: Tobias
authors.initials: T
authors.lastname: Zellweger
authors.forename: Alexander
authors.initials: A
authors.lastname: Bachmann
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Koivisto
authors.forename: Heikki J
authors.initials: HJ
authors.lastname: Helin
authors.forename: Spyro
authors.initials: S
authors.lastname: Mousses
authors.forename: Michael T
authors.initials: MT
authors.lastname: Barrett
authors.forename: David O
authors.initials: DO
authors.lastname: Azorsa
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
mesh_terms: D049109:Cell Proliferation; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D055028:Comparative Genomic Hybridization / Q000379:methods; D018450:Disease Progression; D005784:Gene Amplification; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011470:Prostatic Hyperplasia / Q000378:metabolism; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016596:Vinculin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D016596:Vinculin