This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Turner, B. C. Articles by Popescu, N. C. Search for Related Content PubMed PubMed Citation Articles by Turner, B. C. Articles by Popescu, N. C.

The Fragile Histidine Triad/Common Chromosome Fragile Site 3B Locus and Repair-deficient Cancers¹

Departments of Radiation Oncology [B. C. T., M. P.], Microbiology and Immunology [M. O., C. S., K. H.], Medicine [W. W. H., E. P.], and Pathology [P. A. M., J. P.], Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892 [D. B. Z., C. L. K- W., N. C. P.]; and Department of Carcinogenesis, University of Texas, M. D. Anderson Cancer Center, Science Park Research Division, Smithville, Texas 77030 [C. M. A.]

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.

This article has been cited by other articles:

				A. Helmrich, K. Stout-Weider, K. Hermann, E. Schrock, and T. Heiden Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes Genome Res., October 1, 2006; 16(10): 1222 - 1230. [Abstract] [Full Text] [PDF]

				J. S. Kim, J. W. Kim, J. Han, Y. M. Shim, J. Park, and D.-H. Kim Cohypermethylation of p16 and FHIT Promoters as a Prognostic Factor of Recurrence in Surgically Resected Stage I Non-Small Cell Lung Cancer. Cancer Res., April 15, 2006; 66(8): 4049 - 4054. [Abstract] [Full Text] [PDF]

				M. F. Arlt, B. Xu, S. G. Durkin, A. M. Casper, M. B. Kastan, and T. W. Glover BRCA1 Is Required for Common-Fragile-Site Stability via Its G2/M Checkpoint Function Mol. Cell. Biol., August 1, 2004; 24(15): 6701 - 6709. [Abstract] [Full Text] [PDF]

				S C L Santos, L R Cavalli, I J Cavalli, R S Lima, B R Haddad, and E M S F Ribeiro Loss of heterozygosity of the BRCA1 and FHIT genes in patients with sporadic breast cancer from Southern Brazil J. Clin. Pathol., April 1, 2004; 57(4): 374 - 377. [Abstract] [Full Text] [PDF]

				C. Sevignani, G. A. Calin, R. Cesari, M. Sarti, H. Ishii, S. Yendamuri, A. Vecchione, F. Trapasso, and C. M. Croce Restoration of Fragile Histidine Triad (FHIT) Expression Induces Apoptosis and Suppresses Tumorigenicity in Breast Cancer Cell Lines Cancer Res., March 15, 2003; 63(6): 1183 - 1187. [Abstract] [Full Text] [PDF]

				S. Yendamuri, T. Kuroki, F. Trapasso, A. C. Henry, K. R. Dumon, K. Huebner, N. N. Williams, L. R. Kaiser, and C. M. Croce WW Domain Containing Oxidoreductase Gene Expression Is Altered in Non-Small Cell Lung Cancer Cancer Res., February 15, 2003; 63(4): 878 - 881. [Abstract] [Full Text] [PDF]