Role of the Cdc25A phosphatase in human breast cancer.
The phosphatase Cdc25A plays an important role in cell cycle regulation by removing inhibitory phosphates from tyrosine and threonine residues of cyclin-dependent kinases, and it has been shown to transform diploid murine fibroblasts in cooperation with activated Ras. Here we show that Cdc25A is overexpressed in primary breast tumors and that such overexpression is correlated with higher levels of cyclin-dependent kinase 2 (Cdk2) enzymatic activity in vivo. Furthermore, in the breast cancer cell line MCF-7, Cdc25A activity is necessary for both the activation of Cdk2 and the subsequent induction of S-phase entry. Finally, in a series of small (< 1 cm) breast carcinomas, overexpression of Cdc25A was found in 47% of patients and was associated with poor survival. These data suggest that overexpression of Cdc25A contributes to the biological behavior of primary breast tumors and that both Cdc25A and Cdk2 are suitable therapeutic targets in early-stage breast cancer.
Cangi
M G
MG
Department of Adult Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Cukor
B
B
Soung
P
P
Signoretti
S
S
Moreira
G
G
Ranashinge
M
M
Cady
B
B
Pagano
M
M
Loda
M
M
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016208:Databases, Factual; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006651:Histocytochemistry; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000235:genetics; D015996:Survival Rate; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases