Rare activation of the TCF/beta-catenin pathway in ovarian cancer

Objective. The activation of the T cell factor/beta-catenin pathway is a cr ucial event in colon cancer initiation. A recent report describing the pres ence of beta-catenin mutations in endometrioid ovarian cancer suggested tha t the TCF/beta-catenin pathway may be generally activated in ovarian cancer . We therefore undertook to determine the frequency of activation of this p athway 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/beta-catenin-mediated transcriptional act ivity using a reporter assay. Lines possessing such activity were subjected to mutational and gel-shift analysis, as well as sensitivity to the introd uction of dominant-negative TCF or APC alleles. A cDNA harboring a beta-cat enin point mutation found in an ovarian cancer line was incorporated into a n expression plasmid for functional analysis. Results. Constitutive TCF/beta-catenin transcriptional activity was detecte d 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, UC I107, harbored an activating beta-catenin point mutation, which was shown t o be capable of inducing TCF/beta-catenin transcriptional activity in trans iently transfected 293 cells. A second active line, SW626, was shown to har bor an inactivating APC mutation and may in fact be of colonic origin. The third and fourth lines harbored neither an APC nor a beta-catenin mutation. Gel-shift analysis, together with the absence of sensitivity to dominant-n egative TCF, indicated that the reporter activity exhibited by the latter t wo cell lines may not be due to a TCF/beta-catenin transcriptional complex. Conclusions. These results indicate that genuine constitutive activation of the TCF/beta-catenin pathway is infrequent in ovarian cancer, but that con stitutive transcriptional repression from TCF sites is more common in this tumor type.