The multidrug resistance P-glycoprotein ABCB1 plays a major role in resistance of malignant cells to cancer therapeutics. ABCB1 is regulated by a variety of transcription factors, including NF-kB, AP1, Ras/WT-1, HSF1, HIF-1, and Wnt/b-catenin/TCF4. The canonical Wnt/b-catenin signaling pathway also induces PITX2 (Pituitary homeobox 2), a transcription factor belonging to the bicoid class of homeodomain proteins which is crucial during mammalian development. PITX2 functions by recruiting and interacting with b-catenin to increase the expression of target genes involved in proliferation and survival, such as cyclin D1/2 and c-Myc. However, the importance of PITX2 expression and activity in malignancy has not yet been established. Here we demonstrate that in the renal cancer cell lines ACHN and A498, the level of ABCB1 expression correlates with PITX2 expression, nuclear translocation of PITX2 and PITX2-luciferase reporter gene activity. Moreover, PITX2 overexpression increases ABCB1 expression. In contrast, silencing of PITX2 by siRNA leads to down-regulation of ABCB1 and a greater chemotherapeutic response to doxorubicin in A498 cells, which normally express high levels of ABCB1. Hence, the data indicate for the first time that ABCB1 is a target gene of PITX2 transcriptional activity and thereby promotes multidrug resistance and cell survival. This paves the way for PITX2 as a putative chemotherapeutic target in drug-resistant renal carcinoma. Ongoing experiments aim to identify the PITX2 binding regions of the ABCB1 promoter and to determine the role of b-catenin in PITX2-mediated transcription of ABCB1 using b-catenin^-/- cells. Funded by DFG TH 345/10-1.