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Gadd45a Suppresses Ras-Driven Mammary Tumorigenesis by Activation of c-Jun NH₂-Terminal Kinase and p38 Stress Signaling Resulting in Apoptosis and Senescence

¹ Fels Institute for Cancer Research and Molecular Biology and ² Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Dan A. Liebermann, Fels Institute for Cancer Research and Molecular Biology and Department of Biochemistry, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140. Phone: 215-707-6903; Fax: 215-707-2805; E-mail: lieberma{at}temple.edu.

The Gadd45 family of proteins is known to play a central role as cellular stress sensors that modulate the response of mammalian cells to stress inflicted by physiologic and environmental stressors. Gadd45a was shown to be a direct target to the p53 and BRCA1 tumor suppressor genes, whose loss of function is known to play a vital role in breast carcinogenesis; however, the role of Gadd45a in the suppression of breast cancer remains unclear. To address this issue, Gadd45a-deficient mice were crossed with breast cancer prone mouse mammary tumor virus–Ras mice to generate mice that express activated Ras and differ in their Gadd45a status. Using this mouse model, we show that the loss of Gadd45a accelerates Ras-driven mammary tumor formation, exhibiting increased growth rates and a more aggressive histologic phenotype. Moreover, it is shown that accelerated Ras-driven tumor formation in the absence of Gadd45a results in both a decrease in apoptosis, which is linked to a decrease in c-Jun NH₂-terminal kinase (JNK) activation, and a decrease in Ras-induced senescence, which is correlated with a decrease in p38 kinase activation. Altogether, these results provide a novel model for the tumor-suppressive function of Gadd45a in the context of Ras-driven breast carcinogenesis, showing that Gadd45a elicits its function through activation of the stress-induced JNK and p38 kinases, which contribute to increase in apoptosis and Ras-induced senescence. (Cancer Res 2006; 66(17): 8448-54)

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				Correction: Gadd45a in MMTV-Ras Mammary Tumorigenesis Cancer Res., January 1, 2007; 67(1): 427 - 427. [Full Text] [PDF]