Project Summary

One focus of our current research is the role of BCL9 proteins in the canonical Wnt/beta-catenin signaling pathway in mammals. We have previously identified BCL9-2 in humans, the homolog of the proto-oncogene product BCL9, which plays a crucial role in the switch between beta-catenin’s adhesive and transcriptional functions. The mammalian BCL9 proteins and Legless, the orthologue of Drosophila, are essential components of the canonical Wnt/beta-catenin signaling pathway. BCL9/Legless proteins establish a nuclear complex with beta-catenin/armadillo and enhance Lef/Tcf-/beta-catenin-dependent transcription.

Our research is dedicated to the characterization of the interplay of BCL9 proteins with the Wnt- and other signaling pathways (i.e.  BMP, TGFbeta), to study their role as oncogenes for the initiation and progression of tumors and to analyze target genes of the beta-catenin/BCL9 complex. For this, we apply a broad variety of molecular biology methods in vitro and study in vivo carcinogenesis using genetic models of the mouse.

In the second funding period, we will focus on two aspects based on our results obtained during the first three years:

The first focus will be the target genes of BCL9-2, the second aim has evolved from the tumor development of our BCL9-2 transgenic mice. We will elucidate in depth the transcriptional control and the role of BCL9-2 regulated Wnt-target genes in vitro and in vivo, and other novel target genes identified in our microarrays. We will characterize putative consensus sequences in such target genes, which might be regulated by BCL9-2, either together with ß-catenin or with other signaling molecules. These targets will be further analyzed in vitro and in our BCL9-2 overexpression mouse models in comparison with other mouse tumor models. Moreover, we will characterize the induction of EMT by BCL9-2 and the regulation of E-cadherin expression, which might confer to tumor progression.

Secondly, we will focus on BCL9-2 induced tumorigenesis in human and in mouse models. Human cancers will be analyzed for BCL9-2, and we will perform RNA interference in cultured cancer cells. We will also perform functional analyses on primary cultures of cancers and precancerous tissues from BCL9-2 overexpressing mice. These studies will elucidate the role of BCL9-2 in cancer development and progression.