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.
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Acknowledgements
We thank F Birg and D Maraninchi for encouragements, C Chabannon for biobank sample management and JM Durey for his help with iconography. This work was supported by Institut Paoli-Calmettes, INSERM, and grants from Ligue Nationale Contre le Cancer (LNCC) (Label 2003-2006), the Association pour la Recherche contre le Cancer (ARC-3128) and Ministries of Health and Research (Cancéropôle PACA). SGU, CG and FM are supported by a fellowship from Ministry of Research and AL by a fellowship from LNCC.
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Letessier, A., Garrido-Urbani, S., Ginestier, C. et al. Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer. Oncogene 26, 298–307 (2007). https://doi.org/10.1038/sj.onc.1209772
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DOI: https://doi.org/10.1038/sj.onc.1209772
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