Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer

Oncogene. 2007 Jan 11;26(2):298-307. doi: 10.1038/sj.onc.1209772. Epub 2006 Jul 3.

Abstract

Common fragile sites (CFSs) are regions of chromosomal break that may play a role in oncogenesis. The most frequent alteration occurs at FRA3B, within the FHIT gene, at chromosomal region 3p14. We studied a series of breast carcinomas for break of a CFS at 6q26, FRA6E, and its associated gene PARK2, using fluorescence in situ hybridization on tissue microarrays (TMA). We found break of PARK2 in 6% of cases. We studied the PARK2-encoded protein Parkin by using immunohistochemistry on the same TMA. Loss of Parkin was found in 13% of samples but was not correlated with PARK2 break. PARK2 break but not Parkin expression was correlated with prognosis. Alteration of PARK2/FRA6E may cause haplo-insufficiency of one or several telomeric potential tumor suppressor genes (TSG). The AF-6/MLLT4 gene, telomeric of PARK2, encodes the Afadin scaffold protein, which is essential for epithelial integrity. Loss of Afadin was found in 14.5% of cases, and 36% of these cases showed PARK2 break. Loss of Afadin had prognostic impact, suggesting that AF-6 may be a TSG. Loss of Afadin was correlated with loss of FHIT expression, suggesting fragility of FRA6E and FRA3B in a certain proportion of breast tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Anhydride Hydrolases / genetics*
  • Acid Anhydride Hydrolases / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Blotting, Western
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Carcinoma, Ductal, Breast / diagnosis
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Lobular / diagnosis
  • Carcinoma, Lobular / genetics
  • Carcinoma, Lobular / metabolism
  • Chromosome Breakage*
  • Chromosome Fragile Sites
  • Chromosomes, Human, Pair 6 / genetics
  • Female
  • Fluorescent Antibody Technique
  • Genes, Tumor Suppressor
  • Humans
  • Immunoenzyme Techniques
  • In Situ Hybridization, Fluorescence
  • Kinesin / genetics*
  • Kinesin / metabolism
  • MicroRNAs
  • Middle Aged
  • Myosins / genetics*
  • Myosins / metabolism
  • Neoplasm Invasiveness / pathology
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Prognosis
  • RNA Interference
  • Survival Rate
  • Tissue Array Analysis
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • AFDN protein, human
  • MicroRNAs
  • Neoplasm Proteins
  • fragile histidine triad protein
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Acid Anhydride Hydrolases
  • Myosins
  • Kinesin