The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma.
BACKGROUND
FHIT and WWOX are a tumor suppressor and a candidate suppressor that encompass the FRA3B and FRA16D fragile sites at chromosomes 3p14.2 and 16q23.3-24.1, respectively. Reduced or absent Fhit expression has been reported in two-thirds of invasive breast tumors in association with adverse prognostic factors. Loss of 16q has been reported frequently in low-grade, invasive breast tumors.


METHODS
Expression of Fhit and Wwox was evaluated by immunohistochemical staining in 97 archived breast carcinoma specimens. Expression levels were analyzed for correlations with each other, as well as with various patient and tumor characteristics.


RESULTS
Reduced Fhit and Wwox expression in tumors was observed in 54.6% and 63.2% of specimens, respectively. Fhit and Wwox expression were correlated strongly (P = 0.001). Reduced Fhit staining was seen more frequently in premenopausal patients (P = 0.010), estrogen receptor (ER)-negative or scantly ER-positive tumors (P = 0.058 borderline), high-grade tumors (P = 0.005), and tumors with metastases (P = 0.041). Reduced Wwox staining was more common in tumors with less favorable ER status (P = 0.033). Wwox expression in normal tissue was reduced in 32.9% of specimens, especially in patients with higher stage disease (P = 0.033). Severely reduced Wwox staining (extent < 10%) in normal tissue was found only in postmenopausal women, but reduced Wwox staining (11-75%) was more common in premenopausal women (P = 0.012). Tumor status, lymph node status, and intensity of Fhit expression in tumors were related independently to survival (P = 0.003, P < 0.001, and P = 0.046, respectively).


CONCLUSIONS
The strong correlation observed between Fhit and Wwox expression was consistent with the common elevated susceptibility of fragile sites to DNA damage. Reduced Fhit expression is associated with adverse prognostic factors. The current results suggest that Wwox also has an important and complex association with steroid hormone expression and breast carcinogenesis.
Guler
Gulnur
G
Department of Pathology, Hacettepe University, Ankara, Turkey. gulnurguler@yahoo.com
Uner
Aysegul
A
Guler
Nilufer
N
Han
Shuang-Yin
SY
Iliopoulos
Dimitrios
D
Hauck
Walter W
WW
McCue
Peter
P
Huebner
Kay
K
D017766:Acid Anhydride Hydrolases; D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D002885:Chromosomes, Human, Pair 16; D002893:Chromosomes, Human, Pair 3; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D011379:Prognosis; D011960:Receptors, Estrogen; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D002352:Carrier Proteins; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D000099170:Bis(5'-adenosyl)triphosphatase