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Nonredundant Functions for Tumor Protein D52-Like Proteins Support Specific Targeting of TPD52

Authors' Affiliations: ¹ Molecular Oncology Laboratory, Oncology Research Unit, ² The University of Sydney Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead; ³ Westmead Millennium Institute, Westmead, New South Wales, Australia; ⁴ Laboratoire d'Oncogénétique, INSERM U735, Centre René Huguenin, St-Cloud, France; ⁵ Laboratoire de Génétique Moléculaire, UPRES INSERM U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes-Paris V, Paris, France; ⁶ Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; and ⁷ Department of Microbiology and Immunology and the Southwest Cancer Treatment and Research Center, Texas Tech University Health Sciences Center, Lubbock, Texas

Requests for reprints: Jennifer A. Byrne, Molecular Oncology Laboratory, Oncology Research Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, New South Wales, Australia. Phone: 61-2-9845-3027; Fax: 61-2-9845-3078; E-mail: JennifeB{at}chw.edu.au.

Purpose: Tumor protein D52 (TPD52 or D52) is frequently overexpressed in breast and other cancers and present at increased gene copy number. It is, however, unclear whether D52 amplification and overexpression target specific functional properties of the encoded protein.

Experimental Design: The expression of D52-like genes and MAL2 was compared in breast tissues using quantitative reverse transcription-PCR. The functions of human D52 and D53 genes were then compared by stable expression in BALB/c 3T3 fibroblasts and transient gene knockdown in breast carcinoma cell lines. In situ D52 and MAL2 protein expression was analyzed in breast tissue samples using tissue microarray sections.

Results: The D52 (8q21.13), D54 (20q13.33), and MAL2 (8q24.12) genes were significantly overexpressed in breast cancer tissue (n = 95) relative to normal breast (n = 7; P 0.005) unlike the D53 gene (6q22.31; P = 0.884). Subsequently, D52-expressing but not D53-expressing 3T3 cell lines showed increased proliferation and anchorage-independent growth capacity, and reduced D52 but not D53 expression in SK-BR-3 cells significantly increased apoptosis. High D52 but not MAL2 expression was significantly associated with reduced overall survival in breast carcinoma patients (log-rank test, P < 0.001; n = 357) and was an independent predictor of survival (hazard ratio, 2.274; 95% confidence interval, 1.228-4.210; P = 0.009; n = 328).

Conclusion: D52 overexpression in cancer reflects specific targeting and may contribute to a more proliferative, aggressive tumor phenotype in breast cancer.