The Prostate 67:1081^1090 (2007) Secreted Frizzled-Related Protein 4 Inhibits Proliferation and Metastatic Potential in Prostate Cancer Lisa G. Horvath, 1,2 Jayne E. Lelliott, 2 James G. Kench, 2,3 C.-Soon Lee, 4,5 Elizabeth D. Williams, 6 Darren N. Saunders, 2 John J. Grygiel, 7 Robert L. Sutherland, 2 and Susan M. Henshall 2 * 1 Sydney Cancer Centre, Royal Prince Alfred Hospital,Camperdown, Australia 2 Cancer Research Program,Garvan Institute of Medical Research, St.Vincent’s Hospital, Darlinghurst, Sydney, Australia 3 Department of Tissue Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital,Westmead, Australia 4 Department of Anatomical Pathology, Royal Prince Alfred Hospital,Camperdown, Australia 5 Department of Pathology,University of Sydney,Camperdown, Australia 6 Monash Institute of Medical Research, Monash University,Clayton, Australia 7 Department of Medical Oncology, St.Vincent’s Hospital, Darlinghurst, Sydney, Australia BACKGROUND. Secreted frizzled-related proteins (sFRP4) inhibits Wnt signaling and thus cellular proliferation in androgen-independent prostate cancer cells in vitro. However, increased expression of membranous sFRP4 is associated with a good prognosis in human localized androgen-dependent prostate cancer, suggesting a role for sFRP4 in early stage disease. Here, we investigated the phenotype of sFRP4 overexpression in an androgen- dependent prostate cancer model. METHODS. An sFRP4-overexpressing androgen-dependent (LNCaP) prostate cancer model was established to assess changes in cellular proliferation, the expression, and subcellular localization of adhesion molecules and cellular invasiveness, and compared with the findings in sFRP4-overexpressing androgen-independent cells (PC3). RESULTS. sFRP4 overexpression in both cell line models resulted in a morphologic change to a more epithelioid cell type with increased localization of b-catenin and cadherins (E-cadherin in LNCaP, N-cadherin in PC3) to the cell membrane. Functionally, sFRP4 overexpression was associated with a decreased rate of proliferation (P ¼ 0.0005), decreased anchorage-indepen- dent growth (P < 0.001), and decreased invasiveness in PC3 cells (P < 0.0001). Furthermore, increased membranous sFRP4 expression was associated with increased membranous b- catenin expression (P ¼ 0.02) in a cohort of 224 localized human androgen-dependent prostate cancers. The work was performed at Cancer Research Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Darlinghurst, Sydney, NSW 2010, Australia. No conflicts of interest are associated with this work. Grant sponsor: National Health and Medical Research Council of Australia (NHMRC); Grant sponsor: The Cancer Institute New South Wales; Grant sponsor: Royal Australasian College of Physicians; Grant sponsor: Vincent Fairfax Family Foundation; Grant sponsor: US Department of Defence; Grant sponsor: E. J. Whitten Foundation; Grant sponsor: RT Hall Trust; Grant sponsor: St. Vincent’s Clinic Foundation. *Correspondence to: Susan M. Henshall, PhD, Head, Prostate Cancer, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. E-mail: s.henshall@garvan.org.au Received 21 December 2006; Accepted 26 March 2007 DOI 10.1002/pros.20607 Published online 2 May 2007 in Wiley InterScience (www.interscience.wiley.com). ß 2007 Wiley-Liss, Inc.