Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer.
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.
Letessier
A
A
Centre de Recherche en Cancérologie de Marseille, Département d'Oncologie Moléculaire, UMR599 Inserm et Institut Paoli-Calmettes, Marseille, France.
Garrido-Urbani
S
S
Ginestier
C
C
Fournier
G
G
Esterni
B
B
Monville
F
F
Adélaïde
J
J
Geneix
J
J
Xerri
L
L
Dubreuil
P
P
Viens
P
P
Charafe-Jauffret
E
E
Jacquemier
J
J
Birnbaum
D
D
Lopez
M
M
Chaffanet
M
M
D017766:Acid Anhydride Hydrolases / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D018275:Carcinoma, Lobular / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D019457:Chromosome Breakage; D043283:Chromosome Fragile Sites; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs; D008875:Middle Aged; D009218:Myosins / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D034622:RNA Interference; D015996:Survival Rate; D046888:Tissue Array Analysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D016547:Kinesins; D035683:MicroRNAs; D009218:Myosins; D009363:Neoplasm Proteins; D044767:Ubiquitin-Protein Ligases; D000099170:Bis(5'-adenosyl)triphosphatase; C095516:AFDN protein, human; C111567:parkin protein