Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 7, Pages 2893-2906Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI64410
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Funding
- NIH [CA118306, ES021018, P30 NS045758, T32 CA090223]
- Pelotonia Idea Grant
- National Health and Medical Research Council [535903]
- Australian Cancer Research Foundation
- RT Hall Trust
- Petre Foundation
- Cancer Institute New South Wales Translational Program [10/TPG/1-04]
- Sydney Catalyst Translational Research Centre [11/TRC/1-02]
- Sydney Catalyst Fellowship [10/CRF/1-07]
- Australia and New Zealand Breast Cancer Trials Group
- Sydney Breast Cancer Foundation
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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.
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