Hemizygous Disruption of Cdc25A Inhibits Cellular Transformation and Mammary Tumorigenesis in Mice

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 14; pp. 6605 - 6611
• Main Authors: Ray, Dipankar, Terao, Yasuhisa, Nimbalkar, Dipali, Hirai, Hiroyuki, Osmundson, Evan C., Zou, Xianghong, Franks, Roberta, Christov, Konstantin, Kiyokawa, Hiroaki
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.2007
• Subjects: Animals; Biological and medical sciences; cdc25 Phosphatases - genetics; cdc25 Phosphatases - physiology; Cell Cycle; Cell Transformation, Neoplastic; Cells, Cultured; Fibroblasts - metabolism; G2 Phase; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Mammary gland diseases; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; ras Proteins - metabolism; S Phase; Time Factors; Tumors; Vertebrata; Mammalia; Mouse; Hemizygozity; Animal; Rodentia; Inhibitor; Tumorigenicity; Mammary gland; Malignant tumor; Cell transformation; Carcinogenesis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-4815

CDC25A phosphatase activates multiple cyclin-dependent kinases (CDK) during cell cycle progression. Inactivation of CDC25A by ubiquitin-mediated degradation is a major mechanism of DNA damage-induced S-G2 checkpoint. Although increased CDC25A expression has been reported in various human cancer tissues, it remains unclear whether CDC25A activation is a critical rate-limiting step of carcinogenesis. To assess the role for CDC25A in cell cycle control and carcinogenesis, we used a Cdc25A-null mouse strain we recently generated. Whereas Cdc25A−/− mice exhibit early embryonic lethality, Cdc25A+/− mice show no appreciable developmental defect. Cdc25A+/− mouse embryonic fibroblasts (MEF) exhibit normal kinetics of cell cycle progression at early passages, modestly enhanced G2 checkpoint response to DNA damage, and shortened proliferative life span, compared with wild-type MEFs. Importantly, Cdc25A+/− MEFs are significantly resistant to malignant transformation induced by coexpression of H-rasV12 and a dominant negative p53 mutant. The rate-limiting role for CDC25A in transformation is further supported by decreased transformation efficiency in MCF-10A human mammary epithelial cells stably expressing CDC25A small interfering RNA. Consistently, Cdc25A+/− mice show substantially prolonged latency in mammary tumorigenesis induced by MMTV-H-ras or MMTV-neu transgene, whereas MMTV-myc–induced tumorigenesis is not significantly affected by Cdc25A heterozygosity. Mammary tissues of Cdc25A+/−;MMTV-neu mice before tumor development display less proliferative response to the oncogene with increased tyrosine phosphorylation of CDK1/2, but show no significant change in apoptosis. These results suggest that Cdc25A plays a rate-limiting role in transformation and tumor initiation mediated by ras activation. [Cancer Res 2007;67(14):6605–11]