Transcription factor ATF3 links host adaptive response to breast cancer metastasis
| Autor: | Ewan K.A. Millar, Erik Zmuda, Michael C. Ostrowski, Swati P. Jalgaonkar, Stephen J. McConoughey, Chris C. Wolford, Stephanie L. Roller, Marino E. Leon, Yi-Seok Chang, Robert L. Sutherland, Anand S. Merchant, Tsonwin Hai, Charles L. Shapiro, Sandra A O'Toole, Johnna L. Dominick, Xin Yin |
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| Rok vydání: | 2013 |
| Předmět: |
Lung Neoplasms
Stromal cell Myeloid Gene Expression Breast Neoplasms Kaplan-Meier Estimate Adaptive Immunity Biology Metastasis Mice Breast cancer Stroma Cell Movement Cancer stem cell Human Umbilical Vein Endothelial Cells Tumor Cells Cultured medicine Animals Humans RNA Messenger Oligonucleotide Array Sequence Analysis Mice Knockout Activating Transcription Factor 3 Macrophages General Medicine Gene signature Neoplastic Cells Circulating medicine.disease Acquired immune system Coculture Techniques Tumor Burden Gene Expression Regulation Neoplastic Mice Inbred C57BL medicine.anatomical_structure Matrix Metalloproteinase 9 Tissue Array Analysis Multivariate Analysis Cancer research Female Transcriptome Neoplasm Transplantation Research Article |
| Zdroj: | Journal of Clinical Investigation. 123:2893-2906 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci64410 |
| Popis: | Host response to cancer signals has emerged as a key factor in cancer development; however, the underlying molecular mechanism is not well understood. In this report, we demonstrate that activating transcription factor 3 (ATF3), a hub of the cellular adaptive response network, plays an important role in host cells to enhance breast cancer metastasis. Immunohistochemical analysis of patient tumor samples revealed that expression of ATF3 in stromal mononuclear cells, but not cancer epithelial cells, is correlated with worse clinical outcomes and is an independent predictor for breast cancer death. This finding was corroborated by data from mouse models showing less efficient breast cancer metastasis in Atf3-deficient mice than in WT mice. Further, mice with myeloid cell-selective KO of Atf3 showed fewer lung metastases, indicating that host ATF3 facilitates metastasis, at least in part, by its function in macrophage/myeloid cells. Gene profiling analyses of macrophages from mouse tumors identified an ATF3-regulated gene signature that could distinguish human tumor stroma from distant stroma and could predict clinical outcomes, lending credence to our mouse models. In conclusion, we identified ATF3 as a regulator in myeloid cells that enhances breast cancer metastasis and has predictive value for clinical outcomes. |
| Databáze: | OpenAIRE |
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