Induction of mammary gland hyperplasia in transgenic mice over-expressing human Cdc25B

Abstract

Cdc25 A and B are dual-speci®city phosphatases which have been implicated in neoplastic transformation. Although Cdc25A and Cdc25B have been found to be over-expressed in many cancer cell lines and primary tumors, the physiological roles of Cdc25A and B in vivo are largely unde®ned. To investigate the roles of these proteins in the oncogenic transformation of the mammary gland we used the mouse mammary tumor virus (MMTV) promoter to target over-expression of the Cdc25B transgene in the mammary glands of transgenic mouse lines. Here we report that the over-expression of Cdc25B enhances the proliferation of mammary epithelial cells resulting in the formation of precocious alveolar hyperplasia. At the molecular level, marked increases in cyclin D1 protein have been found in transgenic mammary epithelial cells. The accelerated growth rate of the mammary epithelial cells could also be attributed to the increased levels of cyclin E/cdk2 activity. In addition, a pronounced decrease in apoptosis was also observed during the involution of mammary gland. The reduction of apoptosis during involution correlated well with the reduced expression of c-myc and p53, both of which have been implicated in apoptosis. Taken together, our results clearly indicate that the deregulated expression of Cdc25B generates mammary gland hyperplasia.

Overexpression of Cdc25B, an androgen receptor coactivator, in prostate cancer

“…Overexpression of Cdc25B is observed in various cancer cell lines and human cancers (Nagata et al, 1991;Galaktionov et al, 1995;Gasparotto et al, 1997;Hernandez et al, 1998). In addition, overexpression of Cdc25B in the mammary gland of transgenic mice under the control of MMTV promoter results in alveolar hyperplasia in vivo (Ma et al, 1999a). More importantly, a recent study suggests that it also acts as a coactivator for the steroid receptors (Ma et al, 1999b).…”

Ectopic expression of FGF-3 results in abnormal prostate and Wolffian duct development

“…For histological examination, the slides were stained with Hematoxylin and Eosin or with periodic acid schi (PAS) according to standard protocols. For BrdU incorporation studies, the mice were ®rst given an intraperitoneal injection of BrdU at a dose of 100 mg/g body-weight 2 h prior to sacri®ce to label cells in the S phase and the tissue sections immunostained with a monoclonal BrdU antibody (Zymed) as described previously (Ma et al, 1999). Immunostaining with the Ab669 C-CAM1 (Pu et al, 1999) and PG-21 AR antibodies (Prins and Birch, 1995) were performed accordingly.…”

A Novel Synthetic Inhibitor of CDC25 Phosphatases

“…This overexpression of CDC25A has been observed concomitantly with the loss of other regulators such as p27 in high-grade B-cell non-Hodgkin's lymphomas and may, therefore, possibly contribute to their aggressivity (10). Targeted overexpression of CDC25B in mice is responsible for an increased sensitivity to the carcinogen agent DMBA (11,12). CDC25B is also overexpressed in neurons of Alzheimer's disease patients, and it has been suggested that this might be responsible for an inappropriate activation of mitotic CDK/cyclin complexes resulting in the neurodegenerative process (13).…”