BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic, and angiogenic properties to cancer cells

Mala Mani, Daniel E. Carrasco, Zhang Yunyu, Kohichi Takada, Moshe E. Gatt, Jui Dutta-Simmons, Hiroshi Ikeda, Felipe Diaz-Griffero, Victor Pena-Cruz, Monica Bertagnolli, Lois L. Myeroff, Sanford D. Markowitz, Kenneth C. Anderson, Daniel R. Carrasco

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

Several components of the Wnt signaling cascade have been shown to function either as tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway in oncogenesis and the need for further investigation of Wnt signaling components as potential targets for cancer therapy. Here, using expression profiling analysis as well as in vitro and in vivo functional studies, we show that the Wnt pathway component BCL9 is a novel oncogene that is aberrantly expressed in human multiple myeloma as well as colon carcinoma. We show that BCL9 enhances β-catenin-mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases cell proliferation, migration, invasion, and the metastatic potential of tumor cells by promoting loss of epithelial and gain of mesenchymal-like phenotype. Most importantly, BCL9 knockdown significantly increased the survival of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis through down-regulation of c-Myc, cyclin D1, CD44, and vascular endothelial growth factor expression by tumor cells. Together, these findings suggest that deregulation of BCL9 is an important contributing factor to tumor progression. The pleiotropic roles of BCL9 reported in this study underscore its value as a drug target for therapeutic intervention in several malignancies associated with aberrant Wnt signaling.

Original languageEnglish (US)
Pages (from-to)7577-7586
Number of pages10
JournalCancer Research
Volume69
Issue number19
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Mani, M., Carrasco, D. E., Yunyu, Z., Takada, K., Gatt, M. E., Dutta-Simmons, J., Ikeda, H., Diaz-Griffero, F., Pena-Cruz, V., Bertagnolli, M., Myeroff, L. L., Markowitz, S. D., Anderson, K. C., & Carrasco, D. R. (2009). BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic, and angiogenic properties to cancer cells. Cancer Research, 69(19), 7577-7586. https://doi.org/10.1158/0008-5472.CAN-09-0773