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Fhit Expression Protects Against HER2-Driven Breast tumor Development: Unraveling the Molecular Interconnections

Francesca Bianchi, Elda Tagliabue, Sylvie Ménard and Manuela Campiglio

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The tumor suppressor gene FHIT is inactivated by genetic and epigenetic changes, i.e., loss of heterozygosity or promoter hypermethylation, in common human cancers. We recently showed that Fhit protein levels can be regulated by Fhit proteasome degradation mediated by EGF-dependent activation of EGFR family members, including HER2, whose overexpression is linked to poor prognosis in breast cancer. Analysis of a series of 384 human primary breast carcinomas revealed low/absent Fhit protein levels more frequently in HER2-overexpressing tumors. To test for a possible complementation of the FHIT and HER2 genes, tumor incidence was assessed in mice carrying one inactivated Fhit allele (Fhit+/-) crossed with FVB/N mice carrying the rat HER2/neu proto-oncogene driven by the mouse mammary tumor virus promoter. All Fhit heterozygous mice developed mammary tumors, whereas when both Fhit alleles (Fhit+/+) were present, tumor incidence was reduced in 27% of the mice, which remained tumor-free at 20 months. These findings suggest a protective role for FHIT in HER2-driven mammary tumors. Together, these data argue for the cooperation between Fhit and HER2 in breast carcinogenesis.

Authors

Francesca Bianchi

Fondazione IRCCS-Istituto Nazionale Tumori, Milan, Italy

Elda Tagliabue

Fondazione IRCCS-Istituto Nazionale Tumori, Milan, Italy

Sylvie Ménard

Fondazione IRCCS-Istituto Nazionale Tumori, Milan, Italy

Manuela Campiglio

Fondazione IRCCS-Istituto Nazionale Tumori, Milan, Italy

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.