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A Survivin Gene Signature Predicts Aggressive Tumor Behavior

¹ Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts; ² Department of Surgery (Urology), Yale University School of Medicine, New Haven, Connecticut; and ³ Departments of Urology, Microbiology, Dermatology and Pharmacology, ⁴ NYU Cancer Institute, New York University Medical School, New York, New York

Requests for reprints: Dario C. Altieri, Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, LRB428 364 Plantation Street, Worcester, MA 01605. Phone: 508-856-5775; Fax: 508-856-5792; E-mail: dario.altieri{at}umassmed.edu.

Gene signatures that predict aggressive tumor behavior at the earliest stages of disease, ideally before overt tissue abnormalities, are urgently needed. To search for such genes, we generated a transgenic model of survivin, an essential regulator of cell division and apoptosis overexpressed in cancer. Transgenic expression of survivin in the urinary bladder did not cause histologic abnormalities of the urothelium. However, microarray analysis revealed that survivin-expressing bladders exhibited profound changes in gene expression profile affecting extracellular matrix and inflammatory genes. Following exposure to a bladder carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (OH-BBN), survivin transgenic animals exhibited accelerated tumor progression, preferential incidence of tumors as compared with premalignant lesions, and dramatically abbreviated survival. Conversely, transgenic expression of a survivin Thr³⁴Ala dominant-negative mutant did not cause changes in gene expression or accelerated tumor progression after OH-BBN treatment. Therefore, survivin expression induces global transcriptional changes in the tissue microenvironment that may promote tumorigenesis. Detection of survivin or its associated gene signature may provide an early biomarker of aggressive tumor behavior before the appearance of tissue abnormalities.

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