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 B80% of the breast tumors examined (N ¼ 48) and its protein level is elevated in B50% 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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CCAAT/enhancer-binding proteins (C/EBPs) are a highly conserved family of DNA-binding proteins that regulate cell-specific growth, differentiation, and apoptosis. Here, we show that induction of C/EBP␦ gene expression during G 0 growth arrest is a general property of mammary-derived cell lines. C/EBP␦ is not induced during G 0 growth arrest in 3T3 or IEC18 cells. C/EBP␦ induction is G 0 -specific in mouse mammary epithelial cells; C/EBP␦ gene expression is not induced by growth arrest in the G 1 , S, or G 2 phase of the cell cycle. C/EBP␦ antisense-expressing cells (AS1 cells) maintain elevated cyclin D1 and phosphorylated retinoblastoma protein levels and exhibit delayed G 0 growth arrest and apoptosis in response to serum and growth factor withdrawal. Conversely, C/EBP␦-overexpressing cells exhibited a rapid decline in cyclin D1 and phosphorylated retinoblastoma protein levels, a rapid increase in the cyclin-dependent kinase inhibitor p27, and accelerated G 0 growth arrest and apoptosis in response to serum and growth factor withdrawal. When C/EBP␦ levels were rescued in AS1 cells by transfection with a C/EBP␦ "sense" construct, normal G 0 growth arrest and apoptosis were restored. These results demonstrate that C/EBP␦ plays a key role in the regulation of G 0 growth arrest and apoptosis in mammary epithelial cells.

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