Deregulated CDC25A expression promotes mammary tumorigenesis with genomic instability.
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.
Ray
Dipankar
D
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, 303 East Superior Street, Chicago, IL 60611, USA.
Terao
Yasuhisa
Y
Fuhrken
Peter G
PG
Ma
Zhi-Qing
ZQ
DeMayo
Francesco J
FJ
Christov
Konstantin
K
Heerema
Nyla A
NA
Franks
Roberta
R
Tsai
Sophia Y
SY
Papoutsakis
Eleftherios T
ET
Kiyokawa
Hiroaki
H
D000818:Animals; D005260:Female; D018734:Genes, erbB-2; D011905:Genes, ras; D042822:Genomic Instability; D006801:Humans; D006965:Hyperplasia; D008321:Mammary Glands, Animal / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020687:cdc25 Phosphatases / Q000096:biosynthesis* / Q000235:genetics
C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases