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.
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Acknowledgements
We thank Dr M Stampfer (Lawrence Berkeley National Laboratory) for the HMECs and Dr HG Weed (Ohio State University) for statistical analyses. This work is funded by NIH (RO1 DK064938 to TH) and ADA (7-05-RA-52 to TH), with additional support from NIH P30-NS045758.
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Yin, X., DeWille, J. & Hai, T. A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. Oncogene 27, 2118–2127 (2008). https://doi.org/10.1038/sj.onc.1210861
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DOI: https://doi.org/10.1038/sj.onc.1210861
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