Abstract LB-10: A gene expression signature reflects the regulatory status of Wnt/β-catenin pathway activity

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-04, Vol.71 (8_Supplement), p.LB-10-LB-10
• Main Authors: Wu, Zhong, DiCarlo, John, Wang, Yexun
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-LB-10

Due to limitations of cytotoxic based chemotherapies, current oncology drug development is designed to target specific cellular signaling pathways critical for tumor growth and progression. Such targeted drug development requires specific biomarkers to monitor the activity status of pathway. Compared to the traditional method which relies on one or a few indicators within the pathway constituents, multi-gene expression based methods measure pathway alteration as a function of the downstream effect of pathway regulation on multiple gene expression changes. These downstream gene expression alterations can potentially capture all changes related to any upstream alteration of a pathway component. The Wnt/β-catenin pathway is one of the most frequently altered pathways in a number of human cancers including colorectal carcinomas, melanomas, breast cancer and hepatocellular carcinomas and therefore of major interest to cancer researchers. Activation of the Wnt/β-catenin pathway results in a variety of downstream biological effects and this functional diversity is reflected in gene expression changes. By utilizing Wnt3a stimulation and siRNA mediated β-catenin knockdown in 293H cells followed by gene expression profiling analysis, we identified a list of 64 genes whose expression was upregulated in response to Wnt3a and whose increased expression levels were diminished by treatment with β-catenin siRNA. These 64 Wnt/β-catenin response genes were further evaluated by real-time PCR with 11 samples from a panel of 10 different cell lines either stimulated with Wnt3a and LiCl and/or inhibited with β-catenin siRNA. Sixteen genes were identified as a specific panel of indicators for Wnt/β-catenin pathway regulation using a nearest shrunken centroid classifier method. To further verify the 16 gene signature, we applied the signature to 10 new samples from 9 different cell lines in which 5 samples were stimulated with Wnt3a or LiCl and the rest of them were from cells transfected with β-catenin siRNA. The 16 gene signature predicted the regulatory status of Wnt/β-catenin pathway in these 10 samples with an accuracy of 100%. Our study demonstrates the identification and initial verification of a gene expression signature that can potentially serve to monitor the regulatory status of cellular Wnt/β-catenin pathway activity. The applications presented here are for research use only. Not for use in diagnostic procedures. Citation Format: {Authors}. {Abstract title} [abstract