Transcriptional cooperation between the transforming growth factor-beta and Wnt pathways in mammary and intestinal tumorigenesis.
Transforming growth factor-beta (TGF-beta) and Wnt ligands function in numerous developmental processes, and alterations of both signaling pathways are associated with common pathologic conditions, including cancer. To obtain insight into the extent of interdependence of the two signaling cascades in regulating biological responses, we used an oligonucleotide microarray approach to identify Wnt and TGF-beta target genes using normal murine mammary gland epithelial cells as a model. Combination treatment of TGF-beta and Wnt revealed a novel transcriptional program that could not have been predicted from single ligand treatments and included a cohort of genes that were cooperatively induced by both pathways. These included both novel and known components or modulators of TGF-beta and Wnt pathways, suggesting that mutual feedback is a feature of the coordinated activities of the ligands. The majority of the cooperative targets display increased expression in tumors derived from either Min (many intestinal neoplasia) or mouse mammary tumor virus (MMTV)-Wnt1 mice, two models of Wnt-induced tumors, with nine of these genes (Ankrd1, Ccnd1, Ctgf, Gpc1, Hs6st2, IL11, Inhba, Mmp14, and Robo1) showing increases in both. Reduction of TGF-beta signaling by expression of a dominant-negative TGF-beta type II receptor in bigenic MMTV-Wnt1/DNIIR mice increased mammary tumor latency and was correlated with a decrease in expression of Gpc1, Inhba, and Robo1, three of the TGF-beta/Wnt cooperative targets. Our results indicate that the TGF-beta and Wnt/beta-catenin pathways are firmly intertwined and generate a unique gene expression pattern that can contribute to tumor progression.
Labbé
Etienne
E
Departments of Medical Biophysics and Biochemistry, University of Toronto, 160 College Street, Toronto, Ontario, Canada.
Lock
Lisa
L
Letamendia
Ainhoa
A
Gorska
Agnieszka E
AE
Gryfe
Robert
R
Gallinger
Steven
S
Moses
Harold L
HL
Attisano
Liliana
L
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007739:L Cells; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D060508:Wnt3 Protein
D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D060508:Wnt3 Protein