This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ray, D. Articles by Kiyokawa, H. Search for Related Content PubMed PubMed Citation Articles by Ray, D. Articles by Kiyokawa, H.

Deregulated CDC25A Expression Promotes Mammary Tumorigenesis with Genomic Instability

¹ Department of Molecular Pharmacology and Biological Chemistry and ² Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Departments of ³ Biochemistry and Molecular Genetics and ⁴ Surgical Oncology and ⁵ Research Resources Center, University of Illinois College of Medicine, Chicago, Illinois; ⁶ Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois; ⁷ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; and ⁸ Department of Pathology, Ohio State University, Columbus, Ohio

Requests for reprints: Hiroaki Kiyokawa, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, 303 East Superior Street, Lurie 3-113, Chicago, IL 60611. Phone: 312-503-0699; Fax: 312-503-0700; E-mail: kiyokawa{at}northwestern.edu.

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]

This article has been cited by other articles:

				X. Yang, M. Feng, X. Jiang, Z. Wu, Z. Li, M. Aau, and Q. Yu miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A Genes & Dev., October 15, 2009; 23(20): 2388 - 2393. [Abstract] [Full Text] [PDF]

				J. Jin, X. L. Ang, X. Ye, M. Livingstone, and J. W. Harper Differential Roles for Checkpoint Kinases in DNA Damage-dependent Degradation of the Cdc25A Protein Phosphatase J. Biol. Chem., July 11, 2008; 283(28): 19322 - 19328. [Abstract] [Full Text] [PDF]

				D. Ray and H. Kiyokawa CDC25A Phosphatase: a Rate-Limiting Oncogene That Determines Genomic Stability Cancer Res., March 1, 2008; 68(5): 1251 - 1253. [Abstract] [Full Text] [PDF]

				D. Hanahan, E. F. Wagner, and R. D. Palmiter The origins of oncomice: a history of the first transgenic mice genetically engineered to develop cancer Genes & Dev., September 15, 2007; 21(18): 2258 - 2270. [Abstract] [Full Text] [PDF]