title: Aquaporin 5 expression is frequent in prostate cancer and shows a dichotomous correlation with tumor phenotype and PSA recurrence.
abstract: Aquaporin 5 (AQP5) is an androgen-regulated member of a family of small hydrophobic integral transmembrane water channel proteins regulating cellular water homeostasis and growth signaling. To evaluate its clinical impact and relationship with key genomic alterations in prostate cancer, AQP5 expression was analyzed by immunohistochemistry on a tissue microarray containing 12427 prostate cancers. The analysis revealed weak to moderate immunostaining in normal prostate epithelium. In prostate cancers AQP5 staining levels were more variable and also included completely negative and highly overexpressing cases. Negative, weak, moderate, and strong AQP5 staining was found in 25.0%, 32.5%, 32.5%, and 10.0% of 10239 interpretable tumors. Comparison of AQP5 expression levels with tumor characteristics showed a dichotomous pattern with both high and low staining levels being linked to unfavorable tumor phenotype. AQP5 was negative in 28%, 23%, 24%, and 35% of tumors with Gleason score ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4, while the rate of strongly positive cases continuously increased from 7.0% over 10.0% and 12.0% to 13.0% in cancers with Gleason score ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4. AQP5 expression was also related to ERG positivity and phosphatase and tensin homolog (PTEN) deletion (P < .0001 each). Strong AQP5 positivity was seen in 15.5% of ERG-positive and 5.8% of ERG-negative cancers (P < .0001) as well as in 14.7% of cancers with PTEN deletion and 9.4% of cancers without PTEN deletion. Remarkably, both negativity and strong positivity of AQP5 were linked to unfavorable disease outcome. This was however only seen in subgroups defined by TMPRSS2-ERG fusion and/or PTEN deletion. In summary, AQP5 can be both overexpressed and lost in subgroups of prostate cancers. Both alterations are linked to unfavorable outcome in molecularly defined cancer subgroups. It is hypothesized that this dichotomous role of AQP5 is due to two highly different mechanisms as to how the protein can influence cancer cells, that is, hydraulic motility regulation and Ras/MAPK pathway activation.
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pust
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Kylies
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hube-Magg
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kluth
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Koop
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Grob
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Graefen
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Salomon
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Maria Christina
authors.initials: MC
authors.lastname: Tsourlakis
authors.affiliation: General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Izbicki
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Wittmer
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Hartwig
authors.initials: H
authors.lastname: Huland
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany. Electronic address: r.simon@uke.de.
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Wilczak
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steurer
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Krech
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, D-20246, Germany; Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Germany; General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Melling
mesh_terms: D000328:Adult; D000368:Aged; D051402:Aquaporin 5 / Q000032:analysis / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D000071230:Transcriptional Regulator ERG
chemical_list: C496036:AQP5 protein, human; D051402:Aquaporin 5; D014408:Biomarkers, Tumor; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017430:Prostate-Specific Antigen
keywords: AQP5; Biochemical recurrence; PSA; Prostate cancer; Tissue microarray