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PARKZ<FRA6E and Afadin in breast cancer

A Letessier et al

' n    «■*    - *>    •. *    - w

Afadin positivity    Afadin*    Afadin-

in normal breast    positive tunx>r    negative tumor

Figurę 3 Purkin and Afadin expression in breast eanccr. (At Parkin c\prcssion in normal breast and breast tuinors detennined by IHC on I MA. (a) Nonnal breast tissuc witli Parkin cxprcssion; (b) Tumor willi prescrvcd Parkin cxprcssion (arrow) and (c) Tumor showing loss of Parkin cxprc$$ion. (B) Afadin exprcssion in nonnal breast and breast tu mors detennined by IHC on IMA: (a t Normal breast tissue with Afadin cxpression (arrow); (b| Tumor with Afadin cxprcssion (arrow) and (ct Tumor showing loss of Afadin exprcssion in tumoral componenl (arrow) and Afadin cxpression in normal tissue.

fable 2 List of protcins tested by and charactcrislies of the corresponding antibodics

Protein	Antiboiiyl	Orty ui	Clone	Ditution
Lslrogcn receptor	mmab	Novocastra Laboratories	6111	1 60
Progcstcronc receptor	mmab	DakoCytomation	PgR 636	1.80
LRBB2	rpab	DakoCĄtomation	1 IcrccpTest	1 400
P53	mmab	Immunotech	DO-1	14
MIB1	mmab	DakoCytomation	Ki67	1 100
Parkin	rpa b	Ncomarkers	RB92I5	1/30
Afadin*	mmab	I ransduction Laboratories	35	1/50
Afadin	rmab	HyCult Biotechnolog) b.v	3	1 50
inrr	rpa b	Zymed Laboratories	ZR44	1 300

Abbrcviations: mmab. mousc monoclonal antibody: rpab. rabbit polyelonai antibody; rmab. rat monoclonal antibody: IHC. immunohisto* chcmistry; TMA. tissue microarrays. “This Afadin antibody was used in IHC’ on I MA.

associated with a profound disorganization of cpithclial ccii celi contacts conlirming the fundamcntal role of Afadin in cpithclial physiology prcviously suggested by the studies of knockout mouse tnodels (Ikeda et al.. 1999; Zhadanov et a/.. 1999).

Discussion

Breast cancer is an heterogeneous cancer with inultiplc forms and distinct entilies (Sorlic et al.. 2003; Charafe-Jauffret et al.. 2005). A bet ter under-standing of the molecular basis of this heterogcncity should allow a better management of the discase. A possible molecular substratum for tumor dcvelop-ment and heterogcncity is genetic instability. The identification of a distinct subclass of breast cancer with genomie fragility may help understand discase heterogcncity. This subclass could be recogni/ed by altcralions at CFS.

CFSs are highly unstable genomie regions. Thcy could predispose chromosomes to break, generale chromosomal rearrangements in cancer cells and play a role in tumor initiation and or progression (Huebner et a/.. 1998; Smith et a/.. 1998; Suthcrland et al.. 1998). The cloning and the characterization of FRA6E at 6q26 identilied eight genes associated with this lYagilc sile. Among tliem. PARK2 conlains the most unstable region of IRA6E bet w cen i ts exons 2 8 (Denison et al.. 2003a). PARK2 is a large gcnc that is mutalcd in patienls with autosomal recessive juvcnile Parkinsonism and spans the lelomeric half of FRA6E. PARK2 shows similaritics with the iwo most active CFS-associatcd genes. HUT and lV\VOX. HUT at PRA3B (3pl4) and \V\VOX at FRAI6D (16q23) are both large genes. Tliey both suppress tumor celi growth in vitro and in vivo and havc been classilied as TSCi (Bednarek et a/.. 2001; Paige et al.. 2001; Roz et al.. 2002; Huebner and Croce. 2003; Ishii et al.. 2003; Fabbri et al.. 2005).

Oncogene