ATF3, an adaptive-response gene, enhances TGFβ signaling and cancer-initiating cell features in breast cancer cells

Abstract

SummaryThe 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 TGF in the MCF10CA1a breast cancer cells and plays an integral role for TGF 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 TGF 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 TGF. 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.

Acquisition of Chemoresistance and Other Malignancy-related Features of Colorectal Cancer Cells Are Incremented by Ribosome-inactivating Stress

“…In response to injuries, ATF3 up-regulates a survival factor, heat shock protein HSP27, as well as c-Jun/Fos protein, without which cells will undergo a retarded regeneration after injury (44). Moreover, ATF3 can also facilitate malignant tumor metastasis because EMT-related genes, including TWIST1, FN-1, Snail, and Slug, were also up-regulated by ATF3 (45). In particular, ATF3 gene copy numbers and protein levels are significantly higher in malignant breast tumors (46).…”

“…5C). Because ATF3 enhances EMT phenotype-related genes (45), altered EMT may influence the CSC phenotype and resistance to chemotherapy. There is evidence that ATF3 enhances cancer-initiating cell features, as indicated by its ability to increase the population of CD24 low -CD44 high cells, mammosphere-forming ability, and tumor-initiating frequency in breast cancer (45).…”

“…Because ATF3 enhances EMT phenotype-related genes (45), altered EMT may influence the CSC phenotype and resistance to chemotherapy. There is evidence that ATF3 enhances cancer-initiating cell features, as indicated by its ability to increase the population of CD24 low -CD44 high cells, mammosphere-forming ability, and tumor-initiating frequency in breast cancer (45). Particularly stromal stressors, including pro-inflammatory mediators, endoplasmic reticulum stress, and hypoxia in the tumor microenvironment, occasionally induce expression of ATF3, an adaptive-responsive gene (45,50).…”

“…There is evidence that ATF3 enhances cancer-initiating cell features, as indicated by its ability to increase the population of CD24 low -CD44 high cells, mammosphere-forming ability, and tumor-initiating frequency in breast cancer (45). Particularly stromal stressors, including pro-inflammatory mediators, endoplasmic reticulum stress, and hypoxia in the tumor microenvironment, occasionally induce expression of ATF3, an adaptive-responsive gene (45,50). Therefore, ATF3, as a hub of the procarcinogenic biological network, promotes malignancy by increasing the metastasis and biogenesis of CSC features.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…As a protooncogene, ATF3 expression is elevated in human breast cancer , malignant human prostate cancer (Pelzer et al 2006), malignant Hodgkin's lymphoma (Janz et al 2006), and squamous cell carcinoma ). ATF3 reduces expression of tumor suppressor p53 and its downstream target genes in squamous cell carcinoma ) and transactivates expression of TGFβ genes in breast cancer (Yin et al 2010). In addition, ATF3 represses androgen-dependent genes by inhibiting androgen activity, resulting in prostate cancer development (Wang et al 2012a).…”