The role of the novel BCL9/BCL9-2 oncoproteins in tumorigenesis

• Antragsteller: Professor Dr. Felix H. Brembeck
• Fachliche Zuordnung: Hämatologie, Onkologie
• Förderung: Förderung von 2007 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 45707573

Our current investigations indicated that BCL9-2, a cofactor of canonical Wnt-signaling, might play an essential role in intestinal and mammary tumorigenesis. We have developed Tg(K19-Bcl9-2) mice and found the formation of dedifferentiated intestinal and pancreatic tumors. Compound Tg(K19-Bcl9-2) x APCMin/+ mice showed increased adenoma formation, local invasion and decreased survival. Tg(K19- Bcl9-2) female mice developed premalignant alterations of the breast and well differentiated, ER* mammary cancers consisting of luminal and myoepithelial lineages. BCL9-2 regulated a subset of Wnt/ß-catenin target genes in colon cancer cells and in addition other genes, possibly independently of ß-catenin. In the second funding period, we will elucidate the transcriptional control and the role of BCL9-2 regulated target genes in vitro and in vivo, e.g. of CDX1/CDX2, EphrinB, and other novel target genes identified in our microarrays. Moreover, we will characterize the induction of EMT by SCL9-2 and the regulation of E-cadherin expression. Secondly, we will focus on BCL9-2 induced mammary tumorigenesis in human and in mouse models. Mammary cancer cells will be analyzed for BCL9-2 and hormone receptors expression, and we will perform RNA interference in the cells. We will characterize if ER expression and function is regulated by BCL9-2 In mammary cells. Furthermore, we will analyze primary cultures of mouse breast tissues in biological assays and their responsiveness to steroids and Wnt treatment. Primary cells will be sorted for stem cell markers to identify transformed progenitors and putative cancer stem cells. Sorted stem cells will be further analyzed in vitro and in vivo. These studies will elucidate the role of BCL9-2 in breast cancer development and progression.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 942: WNT signalling in development and tumor progression