Breast Cancer Research and Treatment

, Volume 109, Issue 1, pp 47–54

FBXW7 and DNA copy number instability

  • Kristin N. Byrd
  • Bing Huey
  • Ritu Roydasgupta
  • Jane Fridlyand
  • Antoine M. Snijders
  • Donna G. Albertson
Preclinical Study

Abstract

SKP1-cullin-F-box protein (SCF) type ubiquitin ligases degrade proteins controlling the G1/S transition. Deficiency for FBXW7 (also known as hCDC4), which encodes the F-box protein of the SCF type ubiquitin ligase is associated with genomic instability. Here, we investigated the association of FBXW7 deficiency with chromosomal instability in breast cancer. We screened 49 tumors previously profiled by array CGH for mutations in conserved regions of FBXW7, but found no mutations. Copy number loss of FBXW7, however was associated with enhanced genomic instability in the Complex breast tumor subtype, but instability may not be due to FBXW7 haploinsufficiency, since transcript levels were not reduced in tumors with loss of the locus, whereas reduced expression was observed for other neighboring genes involved in maintenance of genome stability. We also investigated whether cells deficient for FBXW7 showed enhanced instability by challenging cells with methotrexate and assessing numbers of genomic alterations arising in resistant cells. Although methotrexate resistant colonies formed at high frequencies in HCT116 FBXW7+/ and HCT116 FBXW7−/ cells compared to parental HCT116, few copy number alterations were detected in the resistant cells. Taken together these studies suggest that FBXW7 deficiency is unlikely to contribute to the extensive copy number aberrations associated with breast and possibly other tumor types.

Keywords

FBXW7 Genome instability Array CGH 

Supplementary material

10549_2007_9623_MOESM1_ESM.doc (186 kb)
Supplemental Table 1Mutational analysis of FBXW7 in ductal invasive breast tumors. Exons 5-9 and 11 were sequenced in 62 ductal invasive breast tumors analyzed previously by array CGH (Fridlyand et al., 2006). No mutations were found in FBXW7, although single base changes were found in the introns before exon 5 in S0041, exon 7 in S1551, and exon 11 in S0065 (DOC 186 kb)
10549_2007_9623_MOESM2_ESM.xls (1.1 mb)
Supplemental Table 2(XLS 1128 kb)

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Kristin N. Byrd
    • 1
    • 2
  • Bing Huey
    • 2
    • 3
  • Ritu Roydasgupta
    • 2
  • Jane Fridlyand
    • 2
    • 4
  • Antoine M. Snijders
    • 1
    • 2
  • Donna G. Albertson
    • 1
    • 2
    • 3
  1. 1.Cancer Research InstituteUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Comprehensive Cancer CenterUniversity of California San FranciscoSan FranciscoUSA
  3. 3.Department of Laboratory MedicineUniversity of California San FranciscoSan FranciscoUSA
  4. 4.Department of Epidemiology and BiostatisticsUniversity of California San FranciscoSan FranciscoUSA

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