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Aberrant Neuropeptide Y and Macrophage Inhibitory Cytokine-1 Expression Are Early Events in Prostate Cancer Development and Are Associated with Poor Prognosis

¹ Cancer Research Program, Garvan Institute of Medical Research; Departments of ² Urology, ³ Anatomical Pathology, and ⁴ Medical Oncology, and ⁵ Centre for Immunology, St. Vincent's Hospital Darlinghurst, Sydney, New South Wales, Australia; ⁶ Department of Tissue Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales, Australia; ⁷ Douglass Hanly Moir Pathology, North Ryde, New South Wales, Australia; ⁸ Department of Anatomical Pathology, Royal Prince Alfred Hospital, and Department of Pathology, University of Sydney; and ⁹ Department of Medical Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

Requests for reprints: Susan M. Henshall, Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital Darlinghurst, 384 Victoria Street, Sydney, New South Wales 2010 Australia. Phone: 61-2-9295-8326; Fax: 61-2-9295-8321. E-mail: s.henshall{at}garvan.org.au

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. (Cancer Epidemiol Biomarkers Prev 2006;15(4):711–6)

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