1. ¹Centre de Recherche en Cancérologie de Marseille, Département d'Oncologie Moléculaire, UMR599 Inserm et Institut Paoli-Calmettes, Marseille, France
2. ²Hématopoièse Fonctionnelle et Moléculaire, UMR599 Inserm et Institut Paoli-Calmettes, Marseille, France
3. ³Département de Biostatistiques, Institut Paoli-Calmettes, Marseille, France
4. ⁴Département d'Oncologie Médicale, UMR599 Inserm et Institut Paoli-Calmettes, Marseille, France
5. ⁵Département de BioPathologie, Institut Paoli-Calmettes, Marseille, France
6. ⁶Faculté de Médecine, Université de la Méditerranée, Marseille, France

Correspondence: Dr D Birnbaum, UMR599 Inserm, 27 Bd. Leï Roure, 13009 Marseille, France. E-mail: birnbaum@marseille.inserm.fr

⁷These authors contributed equally to this work.

Received 21 December 2005; Revised 27 April 2006; Accepted 22 May 2006; Published online 3 July 2006.

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.