title: Aberrant neuropeptide Y and macrophage inhibitory cytokine-1 expression are early events in prostate cancer development and are associated with poor prognosis.
abstract: Studies to elucidate dysregulated gene expression patterns in premalignant prostate lesions have identified several candidate genes with the potential to be targeted to prevent the development and progression of prostate cancer and act as biomarkers of early disease. Herein, we explored the importance of two proteins, neuropeptide Y (NPY) and macrophage inhibitory cytokine-1 (MIC-1), as biomarkers of preinvasive prostate disease and investigated the relationship of expression to biochemical recurrence following treatment for localized prostate cancer. NPY and MIC-1 protein expression was determined by immunohistochemistry on tissue microarrays containing 1,626 cores of benign, low-grade prostatic intraepithelial neoplasia (PIN), high-grade PIN (HGPIN), and prostate cancer tissue from 243 radical prostatectomy patients. Both NPY and MIC-1 showed higher proportional immunostaining in HGPIN and prostate cancer compared with benign epithelium (P < 0.0001). NPY and MIC-1 immunostaining was higher in low-grade PIN compared with other benign tissues (both P < 0.0001) and was equivalent to immunostaining in HGPIN. NPY immunostaining of prostate cancer was independently associated with relapse, after adjusting for traditional prognostic factors, as a categorical variable in 20% intervals (P = 0.0449-0.0103) and as a continuous variable (P = 0.0017). Low MIC-1 immunostaining (20% categories) was associated with pathologic stage >2C after adjusting for predictors of pathologic stage (P = 0.3894-0.0176). This is the first study to show that altered NPY and MIC-1 expression are significantly associated with prostate cancer progression and suggests that these molecules be developed further as biomarkers in the management of prostate disease.
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: Krishan K
authors.initials: KK
authors.lastname: Rasiah
authors.forename: James G
authors.initials: JG
authors.lastname: Kench
authors.forename: Margaret
authors.initials: M
authors.lastname: Gardiner-Garden
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.forename: David
authors.initials: D
authors.lastname: Golovsky
authors.forename: Phillip C
authors.initials: PC
authors.lastname: Brenner
authors.forename: Raji
authors.initials: R
authors.lastname: Kooner
authors.forename: Gordon F
authors.initials: GF
authors.lastname: O'neill
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Turner
authors.forename: Warick
authors.initials: W
authors.lastname: Delprado
authors.forename: C Soon
authors.initials: CS
authors.lastname: Lee
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Breit
authors.forename: John J
authors.initials: JJ
authors.lastname: Grygiel
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Horvath
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Stricker
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Susan M
authors.initials: SM
authors.lastname: Henshall
mesh_terms: D016207:Cytokines / Q000235:genetics*; D018450:Disease Progression; D015870:Gene Expression; D055436:Growth Differentiation Factor 15; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009478:Neuropeptide Y / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D009478:Neuropeptide Y