TitleATF3, an adaptive-response gene, enhances TGF{beta} signaling and cancer-initiating cell features in breast cancer cells.
Publication TypeJournal Article
Year of Publication2010
AuthorsYin, X, Wolford, CC, Chang, Y-S, McConoughey, SJ, Ramsey, SA, Aderem, A, Hai, T
JournalJ Cell Sci
IssuePt 20
Date Published2010 Oct 15
KeywordsActivating Transcription Factor 3, Breast Neoplasms, CD24 Antigen, Cell Line, Tumor, Chromatin Immunoprecipitation, Epithelial-Mesenchymal Transition, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Hyaluronan Receptors, Immunoblotting, Immunoprecipitation, Neoplastic Stem Cells, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transforming Growth Factor beta

The activating transcription factor 3 (ATF3) gene is induced by a variety of signals, including many of those encountered by cancer cells. We present evidence that ATF3 is induced by TGFβ in the MCF10CA1a breast cancer cells and plays an integral role for TGFβ to upregulate its target genes snail, slug and twist, and to enhance cell motility. Furthermore, ATF3 upregulates the expression of the TGFb gene itself, forming a positive-feedback loop for TGFβ signaling. Functionally, ectopic expression of ATF3 leads to morphological changes and alterations of markers consistent with epithelial-to-mesenchymal transition (EMT). It also leads to features associated with breast-cancer-initiating cells: increased CD24(low)-CD44(high) population of cells, mammosphere formation and tumorigenesis. Conversely, knockdown of ATF3 reduces EMT, CD24(low)-CD44(high) cells and mammosphere formation. Importantly, knocking down twist, a downstream target, reduces the ability of ATF3 to enhance mammosphere formation, indicating the functional significance of twist in ATF3 action. To our knowledge, this is the first report demonstrating the ability of ATF3 to enhance breast cancer-initiating cell features and to feedback on TGFβ. Because ATF3 is an adaptive-response gene and is induced by various stromal signals, these findings have significant implications for how the tumor microenvironment might affect cancer development.

Alternate JournalJ Cell Sci
PubMed ID20930144
PubMed Central IDPMC2951469
Grant ListR01 CA118306 / CA / NCI NIH HHS / United States
DK064938S1 / DK / NIDDK NIH HHS / United States
P30 NS045758 / NS / NINDS NIH HHS / United States
R01 DK064938 / DK / NIDDK NIH HHS / United States
R01 AI025032 / AI / NIAID NIH HHS / United States
P30-NS045758 / NS / NINDS NIH HHS / United States