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Fhit loss in familial breast cancer: is loss of DNA repair function linked to alterations at chromosome fragile sites?

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The FHIT gene at 3p14.2 encompasses the common fragile site, FRA3B, and is involved in frequent chromosome rearrangements in human cancers. Fhit protein expression is reduced or lost in the majority of esophageal, lung, gastric, cervical, pancreatic, kidney and bladder cancers, and a large fraction of other cancers. Fhit expression in sporadic breast cancers has been studied by several groups, and reported to show alteration in expression of Fhit in 30-50%. Because familial breast cancers were reported to show a higher frequency of LOH at 3p14.2 than sporadic breast cancers, we were interested in whether common fragile regions might be targets for repair by the Brca1 and Brca2 proteins, and might thus be a downstream target in BRCA1- and BRCA2-induced familial breast tumors. We studied a panel of Brca2-deficient breast tumors and showed that only 18% expressed Fhit strongly, compared with 48% of sporadic tumors (P = 0.002). Very recently we completed a similar study of BRCA1 familial tumors, and observed that only 9% of these tumors showed strong expression versus more than 40% of sporadic breast tumors (P <0.001, odds ratio 0.09). We conclude that loss of BRCA1 and BRCA2 functions affect stability of the FHIT/FRA3B locus and possibly other fragile loci.

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  • Fragile Site
  • Familial Breast Cancer
  • Sporadic Breast Cancer
  • Common Fragile Site
  • FHIT Gene