A survivin gene signature predicts aggressive tumor behavior.
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 Thr34-->Ala 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.
Salz
Whitney
W
Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Eisenberg
Dan
D
Plescia
Janet
J
Garlick
David S
DS
Weiss
Robert M
RM
Wu
Xue-Ru
XR
Sun
Tung-Tien
TT
Altieri
Dario C
DC
D000818:Animals; D002085:Butylhydroxybutylnitrosamine; D002273:Carcinogens; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics*; D009363:Neoplasm Proteins; D016133:Polymerase Chain Reaction; D000077022:Survivin; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D060170:Uroplakin II
C107489:BIRC5 protein, human; D002273:Carcinogens; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C554658:UPK2 protein, human; C554659:Upk2 protein, mouse; D060170:Uroplakin II; D002085:Butylhydroxybutylnitrosamine