1. ¹The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA
2. ²Department of Molecular and Cellular Biochemistry, Neurobiotechnology Center, The Ohio State University, Columbus, OH, USA
3. ³Center for Molecular Neurobiology, The Ohio State University, Columbus, OH, USA
4. ⁴Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA

Correspondence: Professor T Hai, Department of Molecular and Cellular Biochemistry, Neurobiotechnology Center, The Ohio State University, Columbus, 174 Rightmire Hall, 1060 Carmack Road, Columbus, OH 43210, USA. E-mail: hai.2@osu.edu.

Received 30 July 2007; Revised 18 September 2007; Accepted 19 September 2007; Published online 22 October 2007.

Abstract

Activating transcription factor 3 (ATF3) is a member of the ATF/cyclic AMP response element-binding family of transcription factors. We present evidence that ATF3 has a dichotomous role in cancer development. By both gain- and loss-of-function approaches, we found that ATF3 enhances apoptosis in the untransformed MCF10A mammary epithelial cells, but protects the aggressive MCF10CA1a cells and enhances its cell motility. Array analyses indicated that ATF3 upregulates the expression of several genes in the tumor necrosis factor pathway in the MCF10A cells but upregulates the expression of several genes implicated in tumor metastasis, including TWIST1, fibronectin (FN)-1, plasminogen activator inhibitor-1, urokinase-type plasminogen activator, caveolin-1 and Slug, in the MCF10CA1a cells. We present evidence that ATF3 binds to the endogenous promoters and regulates the transcription of the TWIST1, FN-1, Snail and Slug genes. Furthermore, conditioned medium experiments indicated that ATF3 has a paracrine/autocrine effect, consistent with its upregulation of genes encoding secreted factors. Finally, ATF3 gene copy number is >2 in 80% of the breast tumors examined (N=48) and its protein level is elevated in 50% of the tumors. These results provided a correlative argument that it is advantageous for the malignant cancer cells to express ATF3, consistent with its oncogenic roles suggested by the MCF10CA1a cell data.