200 DEFINING THE MECHANISTIC BASIS OF SPOP MUTATIONS IN PROSTATE CANCER (2013)

You have accessJournal of UrologyProstate Cancer: Basic Research (I)1 Apr 2013200 DEFINING THE MECHANISTIC BASIS OF SPOP MUTATIONS IN PROSTATE CANCER Christopher Barbieri, Mirjam Blattner, Limei Xu, Francesca Demichelis, Sylvan Baca, Michael Lawrence, Gunther Boysen, Jean-Philippe Theurillat, Ashutosh Tewari, Pengbo Zhou, Levi Garraway, and Mark Rubin Christopher BarbieriChristopher Barbieri New York, NY More articles by this author , Mirjam BlattnerMirjam Blattner New York, NY More articles by this author , Limei XuLimei Xu New York, NY More articles by this author , Francesca DemichelisFrancesca Demichelis Trento, Italy More articles by this author , Sylvan BacaSylvan Baca Cambridge, MA More articles by this author , Michael LawrenceMichael Lawrence Cambridge, MA More articles by this author , Gunther BoysenGunther Boysen New York, NY More articles by this author , Jean-Philippe TheurillatJean-Philippe Theurillat Cambridge, MA More articles by this author , Ashutosh TewariAshutosh Tewari New York, NY More articles by this author , Pengbo ZhouPengbo Zhou New York, NY More articles by this author , Levi GarrawayLevi Garraway Cambridge, MA More articles by this author , and Mark RubinMark Rubin New York, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1580AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We have recently discovered recurrent mutations in SPOP in up to 15% of prostate cancer (PCA); these are the most common non-synonymous mutations in clinically localized prostate cancer. The SPOP gene encodes the substrate-recognition component of a Cullin3-based E3-ubiquitin ligase. Recurrent missense mutations are found exclusively in the structurally-defined substrate-binding cleft of SPOP, and structural analysis suggests that these mutations disrupt SPOP-substrate interactions. Tumors harboring SPOP mutations display characteristic genomic aberrations, and lack other genetic lesions that are common in PCA. Therefore, recurrent SPOP mutations define a novel molecular subclass of PCA. Determining the altered substrate specificity and downstream signaling of mutant SPOP is key to understanding the functional role of SPOP mutations in prostate cancer. SPOP has a number of known substrates, including SRC-3 (encoded by the gene NCOA3), a steroid receptor co-activator that interacts with AR and regulates expression of androgen-regulated genes and other genes involved in PCA tumorigenesis. METHODS Cell lines were transfected with SPOP mutants and controls. SPOP/SRC-3 interaction was assessed by immunoprecipitation and Western blot. Genomic analysis was performed on 122 human prostate tumors characterized for somatic copy number aberrations and SPOP mutation status. RESULTS Our preliminary studies indicate that SRC-3 is a bona fide substrate of SPOP in PCA cells, and that SPOP mutation results in increased expression of SRC-3. Genomic analysis provides further rationale for investigating the relationship of SPOP mutations with this pathway in PCA. NCOA2 (encoding SRC-2), a close homolog of NCOA3, is recurrently amplified in PCA. NCOA2 amplification is associated with the same pattern of genomic deletions (5q21.1 and 6q21) as SPOP mutation; however, SPOP mutations and NCOA2 amplification rarely occur together suggesting these events may act as “hits” in the same signaling pathway. CONCLUSIONS SPOP mutation represents the most common point mutation in human prostate cancer. SRC-3 is a substrate of SPOP in prostate cancer cells, and SPOP mutations result in increased expression of SRC-3. Furthermore, genomic analysis suggests that SPOP and the SRC pathway are functionally redundant. Ongoing studies will further define substrate specificity and dysregulated downstream signaling pathways in SPOP mutant tumors, and further elucidate the role of cooperative events such as CHD1 deletion. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e82-e83 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Barbieri New York, NY More articles by this author Mirjam Blattner New York, NY More articles by this author Limei Xu New York, NY More articles by this author Francesca Demichelis Trento, Italy More articles by this author Sylvan Baca Cambridge, MA More articles by this author Michael Lawrence Cambridge, MA More articles by this author Gunther Boysen New York, NY More articles by this author Jean-Philippe Theurillat Cambridge, MA More articles by this author Ashutosh Tewari New York, NY More articles by this author Pengbo Zhou New York, NY More articles by this author Levi Garraway Cambridge, MA More articles by this author Mark Rubin New York, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...