Rare Activation of the TCF/β-Catenin Pathway in Ovarian Cancer

Objective.The activation of the T cell factor/β-catenin pathway is a crucial event in colon cancer initiation. A recent report describing the presence of β-catenin mutations in endometrioid ovarian cancer suggested that the TCF/β-catenin pathway may be generally activated in ovarian cancer. We therefore undertook to determine the frequency of activation of this pathway in ovarian cancer cell lines using a functional screen. Methods. We functionally screened a series of ovarian cancer cell lines for the presence of constitutive TCF/β-catenin-mediated transcriptional activity using a reporter assay. Lines possessing such activity were subjected to mutational and gel-shift analysis, as well as sensitivity to the introduction of dominant-negative TCF or APC alleles. A cDNA harboring a β-catenin point mutation found in an ovarian cancer line was incorporated into an expression plasmid for functional analysis. Results. Constitutive TCF/β-catenin transcriptional activity was detected in 21% (4 of 19) of ovarian lines studied, while 32% (6 of 19) exhibited greater than twofold repression. One of the constitutively active lines, UCI107, harbored an activating β-catenin point mutation, which was shown to be capable of inducing TCF/β-catenin transcriptional activity in transiently transfected 293 cells. A second active line, SW626, was shown to harbor an inactivating APC mutation and may in fact be of colonic origin. The third and fourth lines harbored neither an APC nor a β-catenin mutation. Gel-shift analysis, together with the absence of sensitivity to dominant-negative TCF, indicated that the reporter activity exhibited by the latter two cell lines may not be due to a TCF/β-catenin transcriptional complex. Conclusions. These results indicate that genuine constitutive activation of the TCF/β-catenin pathway is infrequent in ovarian cancer, but that constitutive transcriptional repression from TCF sites is more common in this tumor type.