Reference SummaryRay D, Cancer Res 2007 Feb 1;67(3):984-91
Title |
Deregulated CDC25A expression promotes mammary tumorigenesis with genomic instability. |
Authors |
Ray D; Terao Y; Fuhrken PG; Ma ZQ; DeMayo FJ; Christov K; Heerema NA; Franks R; Tsai SY; Papoutsakis ET; Kiyokawa H |
Journal |
Cancer Res |
Volume |
67 |
Issue |
3 |
Year |
2007 |
Pages |
984-91 |
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. |
Links |
J:118218 – MGI References 17283130 – National Library of Medicine/PubMed |
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| FVB/N-Tg(MMTV-Erbb2)NK1Mul | Mammary gland adenocarcinoma | Mammary gland |
observed |
||
| FVB/N-Tg(MMTV-CDC25A)#Tsa Tg(MMTV-Erbb2)NK1Mul | Mammary gland adenocarcinoma - ductal - micropapillary | Mammary gland |
observed |
||
| FVB/N-Tg(MMTV-CDC25A)#Tsa | Mammary gland hyperplasia - alveolar | Mammary gland |
observed |
||
| FVB/N-Tg(MMTV-CDC25A)#Tsa | Mammary gland tumor | Mammary gland |
0 |
||
| [not specified]-Tg(MMTV-CDC25A)#Tsa Tg(MMTV-vHaras)SH1Led | Mammary gland tumor | Mammary gland |
100 |
||
| [not specified]-Tg(MMTV-vHaras)SH1Led | Mammary gland tumor | Mammary gland |
100 |
||
| FVB/N-Tg(MMTV-CDC25A)#Tsa Tg(MMTV-Erbb2)NK1Mul | Mammary gland tumor | Mammary gland |
100 |
||
| FVB/N-Tg(MMTV-Erbb2)NK1Mul | Mammary gland tumor | Mammary gland |
96 |