The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers.
In various studies of sporadic breast cancers, 40-70% were strongly positive for fragile histidine triad (Fhit) protein expression, whereas only 18% of BRCA2 mutant breast cancers demonstrated strong Fhit expression, suggesting that the BRCA2 repair function may be necessary to retain intact fragile common chromosome fragile site 3B(FRA3B)/FHITloci. In the current study, 22 breast tumors with deleterious BRCA1 mutations were analyzed for Fhit expression by immunohistochemistry in a case-control matched pair analysis. Loss of Fhit expression was significantly more frequent in the BRCA1 cancers compared with sporadic breast tumors (9% Fhit positive versus 68% Fhit positive), suggesting that the BRCA1 pathway is also important in protecting the FRA3B/FHIT locus from damage. To investigate the relationship between repair gene deficiencies and induction of chromosome fragile sites in vitro, we have analyzed the frequency of aphidicolin induction of chromosome gaps and breaks in PMS2-, BRCA1-, MSH2-, MLH1-, FHIT-, and TP53-deficient cell lines. Each of the repair-deficient cell lines showed elevated expression of chromosome gaps and breaks, consistent with the proposal that proteins involved in mismatch and double-strand break repair are important in maintaining the integrity of common fragile regions. Correspondingly, genes at common fragile sites may sustain elevated levels of DNA damage in cells with deficient DNA repair proteins such as those mutated in several familial cancer syndromes.
Department of Radiation Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Bruce C
BC
Turner
Michelle
M
Ottey
Drazen B
DB
Zimonjic
Magdalena
M
Potoczek
Walter W
WW
Hauck
Edward
E
Pequignot
Catherine L
CL
Keck-Waggoner
Cinzia
C
Sevignani
C Marcelo
CM
Aldaz
Peter A
PA
McCue
Juan
J
Palazzo
Kay
K
Huebner
Nicholas C
NC
Popescu
D017766:Acid Anhydride Hydrolases; D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D019313:BRCA1 Protein / Q000172:deficiency*; D001943:Breast Neoplasms / Q000235:genetics*; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D004260:DNA Repair / Q000235:genetics*; D020868:Gene Silencing; D019398:Genes, BRCA1; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D014407:Tumor Cells, Cultured; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D016590:Aphidicolin; D019313:BRCA1 Protein; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase