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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Article

Role of the Cdc25A phosphatase in human breast cancer

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 1

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Cdc25A expression levels are directly correlated with Cdk2 activity. (a)...
Cdc25A expression levels are directly correlated with Cdk2 activity. (a) Cdc25A and Gsα mRNA levels were determined by semiquantitative RT-PCR analysis (upper panel) on microdissected frozen tissue samples of breast carcinomas and on MCF-7 cells. Four representative cases of high expressers (lanes 1 and 2) and low expressers (lanes 3 and 4) for Cdc25A are shown. Cdk2 enzymatic activity and Cdk2 protein level for the four tissue samples of breast carcinoma (lanes 1–4), for MCF-7 cells, and for the control sample HeLa cells are shown in the lower panel. A direct correlation between Cdc25A levels and Cdk2 enzymatic activity is evident, whereas Cdk2 levels remain unchanged. (b) Bar graph representing cumulative data of Cdc25A levels compared with Cdk2 enzymatic activity in 21 patients. The ratio of the densitometric values of Cdc25A to those of Gsα was calculated, and the median value was used as a cutoff for the categorization of cases into high and low/nonexpressers. High expressers (+) and low/nonexpressers (–) for Cdc25A were correlated with the corresponding Cdk2 enzymatic activity. To normalize densitometric values of Cdk2 activity, a ratio of the percent area of the tested samples to the one obtained with the HeLa control in each gel was used. To account for variability from gel to gel, this ratio was, in turn, related as a ratio to the total area under all curves in a given gel.