Deregulated CDC25A Expression Promotes Mammary Tumorigenesis with Genomic Instability

Abstract

Checkpoint pathways help cells maintain genomic integrity, delaying cell cycle progression in response to various risks of fidelity, such as genotoxic stresses, compromised DNA replication, and impaired spindle control. Cancer cells frequently exhibit genomic instability, and recent studies showed that checkpoint pathways are likely to serve as a tumor-suppressive barrier in vivo. The cell cycle-promoting phosphatase CDC25A is an activator of cyclin-dependent kinases and one of the downstream targets for the CHK1-mediated checkpoint pathway. Whereas CDC25A overexpression is observed in various human cancer tissues, it has not been determined whether deregulated CDC25A expression triggers or promotes tumorigenesis in vivo. Here, we show that transgenic expression of CDC25A cooperates markedly with oncogenic ras or neu in murine mammary tumorigenesis. MMTV-CDC25A transgenic mice exhibit alveolar hyperplasia in the mammary tissue but do not develop spontaneous mammary tumors. The MMTV-CDC25A transgene markedly shortens latency of tumorigenesis in MMTV-ras mice. The MMTV-CDC25A transgene also accelerates tumor growth in MMTV-neu mice with apparent cell cycle miscoordination. CDC25A-overexpressing tumors, which invade more aggressively, exhibit various chromosomal aberrations on fragile regions, including the mouse counterpart of human 1p31-36, according to array-based comparative genomic hybridization and karyotyping. The chromosomal aberrations account for substantial changes in gene expression profile rendered by transgenic expression of CDC25A, including down-regulation of Trp73. These data indicate that deregulated control of cellular CDC25A levels leads to in vivo genomic instability, which cooperates with the neu-ras oncogenic pathway in mammary tumorigenesis. [Cancer Res 2007;67(3):984-91]

NEK11−Linking CHK1 and CDC25A in DNA damage checkpoint signaling

“…CDC25A is overexpressed in a number of tumors, and mouse models indicate a rate-limiting role for CDC25A in tumorigenesis. 41,42 Thus, it could be interesting to investigate if there is an inverse correlation between CDC25A and NEK11 in primary tumors.…”

IRC‐083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells

“…3,4 Further, hemizygous disruption of CDC25A inhibits cellular transformation and mammary tumorigenesis in mice, suggesting that a low level of CDC25A protein plays a rate-limiting role in transformation and tumor initiation mediated by oncogene such as H-ras 12 and neu. 5,6 Finally, overexpression of CDC25A and CDC25B proteins has been observed in a wide variety of human tumors (see ref. 2 and 7 for review), and these observations have often been linked to a poor prognosis, suggesting an important role in tumor behavior.…”

CDC25A Levels Determine the Balance of Proliferation and Checkpoint Response

“…25 In another recent study using MMTV-CDC25A transgenic mice we demonstrated that CDC25A overexpression in the mouse mammary gland is insufficient to cause spontaneous tumors but does cooperate with neu or ras oncogene. 37 The MMTV-CDC25A transgene significantly accelerates MMTV-ras or -neu-induced mammary tumorigenesis, in association with mis-coordinated cell cycle progression with enhanced genomic instability. Furthermore, Cdc25A heterozygous (+/-) knockout mice are significantly resistant to MMTV-neu or -ras induced oncogenesis.…”