The gene FHIT, encompassing the FRA3B fragile site, is located in a region of chromosome 3p14.2 that is often deleted in several types of epithelial cancers and, therefore, it has been investigated as a candidate tumor suppressor. In breast cancer inactivation of FHIT occurred in 70% of the patients, and it is caused by both alterations in the regulation of Fhit expression and by deletions of the gene. Moreover, analysis of 500 cases of breast carcinomas with 20 years of follow up demonstrated that loss of Fhit protein is associated with high proliferative, large and undifferentiated tumors, even though Fhit is not a prognostic factor. In order to elucidate the possible role of FHIT as a tumor suppressor in breast cancer and to identify its mechanisms, Fhit protein-negative breast cancer cell lines lacking endogenous protein expression were stable transfected with FHIT cDNA. Stable transfectant clones showed no alteration in cell morphology and in in vitro anchorage-dependent and independent proliferation. A significant delay in the tumor growth in nude mice was observed for some Fhit-positive clones; in an additional case the outgrowing of the tumor was due to loss of Fhit expression in vivo. Interestingly, some Fhit-positive clones are able to develop tumors in vivo despite high stable Fhit expression, prompting us to investigate the different mechanisms between the two types of Fhit-expressing clones.

Supported by AIRC.