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Role of the Cdc25A phosphatase in human breast cancer
M. Giulia Cangi, … , Michele Pagano, Massimo Loda
M. Giulia Cangi, … , Michele Pagano, Massimo Loda
Published September 15, 2000
Citation Information: J Clin Invest. 2000;106(6):753-761. https://doi.org/10.1172/JCI9174.
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Role of the Cdc25A phosphatase in human breast cancer

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Abstract

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.

Authors

M. Giulia Cangi, Barry Cukor, Peggy Soung, Sabina Signoretti, Gilberto Moreira Jr., Moksha Ranashinge, Blake Cady, Michele Pagano, Massimo Loda

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Figure 4

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Inactivation of Cdc25A inhibits S-phase entry in breast carcinoma cells....
Inactivation of Cdc25A inhibits S-phase entry in breast carcinoma cells. (a) S phase in MCF-7 cells is measured by FACS analysis of BrdU-stained cells. Antisense oligonucleotides inhibit S-phase entry by 31% at 24 hours and 43% at 48 hours after AS transfection. No change is noted after transfection with scrambled oligonucleotides. S-phase entry is restored by the cotransfection of the nonphosphorylatable mutant of Cdk2, Cdk2AF, and antisense oligonucleotides to Cdc25A. (b) Nonphosphorylatable Cdk2 catalytic mutant (Cdk2AF) abolishes Cdc25A antisense effects on MCF-7. MCF-7 cells were transfected with antisense Cdc25A (AS), wild-type Cdk2 (Cdk2WT), or Cdk2AF, or cotransfected with AS and Cdk2AF or AS and Cdk2WT. Untransfected proliferating MCF-7 cells represent base-line values of Cdk2 activity and S-phase fraction (Control). At 48 hours after transfection, Cdk2 kinase activity (a) and BrdU incorporation as a measure of S-phase fraction (b) show that Cdk2AF, but not Cdk2WT, abolishes the Cdc25A AS effect.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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