Nudix-type motif 2 in human breast carcinoma: a potent prognostic factor associated with cell proliferation.
Nudix-type motif 2 (NUDT2) hydrolyzes diadenosine 5',5'''-p1,p4-tetraphosphate (Ap4A) associated with various cellular functions. Previous studies demonstrated its regulation through estrogens, suggesting possible importance of NUDT2 in breast carcinoma. NUDT2, however, has not been examined in malignant tissues. Therefore, we examined its expression and functions in breast carcinoma. Immunohistochemistry for NUDT2 was examined by invasive ductal carcinoma (IDC: n = 145) and pure ductal carcinoma in situ (DCIS: n = 82), and NUDT2 mRNA was examined by real-time PCR in 9 DCIS, 19 IDC and 6 non-neoplastic breast tissues. We also used T47D breast carcinoma cells in in vitro studies. NUDT2 immunoreactivity was detected in 78% of DCIS and 63% of IDC, and NUDT2 mRNA level was significantly higher in DCIS or IDC than non-neoplastic breast. NUDT2 status was significantly correlated with Van Nuys classification, HER2 or Ki-67 in DCIS, and with stage, lymph node metastasis, histological grade or HER2 in IDC. NUDT2 status was significantly associated with adverse clinical outcome of IDC patients and proved an independent prognostic factor. Results of transfection experiments demonstrated that proliferation activity of T47D cells was significantly associated with NUDT2 expression level according to the treatment of estradiol and/or tamoxifen. NUDT2 expression was significantly decreased by estradiol, and it was also significantly decreased in T47D cells transfected with HER2 siRNA. These findings suggest that NUDT2 is an estrogen-repressed gene and is also induced by HER2 pathways in breast carcinoma cells. NUDT2 promotes proliferation of breast carcinoma cells and is a potent prognostic factor in human breast carcinomas.
Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Kimako
K
Oka
Takashi
T
Suzuki
Yoshiaki
Y
Onodera
Yasuhiro
Y
Miki
Kiyoshi
K
Takagi
Shuji
S
Nagasaki
Jun-Ichi
J
Akahira
Takanori
T
Ishida
Mika
M
Watanabe
Hisashi
H
Hirakawa
Noriaki
N
Ohuchi
Hironobu
H
Sasano
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult; D000096964:Nudix Hydrolases
D010744:Phosphoric Monoester Hydrolases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C557514:NUDT2 protein, human; D000096964:Nudix Hydrolases