Induction of mammary gland hyperplasia in transgenic mice over-expressing human Cdc25B.
Cdc25 A and B are dual-specificity 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 undefined. 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.
Ma
Z Q
ZQ
Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, TX 77030, USA.
Chua
S S
SS
DeMayo
F J
FJ
Tsai
S Y
SY
D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D005260:Female; D016193:G1 Phase; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D006965:Hyperplasia; D008321:Mammary Glands, Animal / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011817:Rabbits; D016196:S Phase; D020687:cdc25 Phosphatases
D018797:Cell Cycle Proteins; D010749:Phosphoprotein Phosphatases; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases