Transcription factor ATF3 links host adaptive response to breast cancer metastasis
Chris C. Wolford, … , Robert L. Sutherland, Tsonwin Hai
Chris C. Wolford, … , Robert L. Sutherland, Tsonwin Hai
Published June 10, 2013
Citation Information: J Clin Invest. 2013;123(7):2893-2906. https://doi.org/10.1172/JCI64410.
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Research Article Oncology

Transcription factor ATF3 links host adaptive response to breast cancer metastasis

Abstract

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.

Authors

Chris C. Wolford, Stephen J. McConoughey, Swati P. Jalgaonkar, Marino Leon, Anand S. Merchant, Johnna L. Dominick, Xin Yin, Yiseok Chang, Erik J. Zmuda, Sandra A. O’Toole, Ewan K.A. Millar, Stephanie L. Roller, Charles L. Shapiro, Michael C. Ostrowski, Robert L. Sutherland, Tsonwin Hai

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Figure 1

ATF3 expression in human breast tumors correlates with worse patient outcome.

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ATF3 expression in human breast tumors correlates with worse patient ou...
(A) Patients from 2 independent RNA microarray datasets — Sorlie et al. (54) and van’t Veer et al. (55) — were arbitrarily classified into ATF3-high (above median) and ATF3-low (below median) groups. Kaplan-Meier curves of their 5-year survival are shown. (B) Same as A, except from a dataset with lung metastasis-free survival rate (56). (C) Serial sections of human breast tumors were analyzed by immunohistochemistry for ATF3 or pan-keratin (an epithelial marker) and counterstained with hematoxylin. Arrow indicates ATF3 staining in the stroma. (D) Immunohistochemistry signals in a tumor microarray was scored by a pathologist in a blinded fashion using the Allred system. Kaplan-Meier survival curves for high (score > 4) and low ATF3 expression in mononuclear cells are shown. (E) Same as C, except ATF3 and CD68 (a macrophage marker) were analyzed. Red outlines indicate a cluster of TAMs. (F and G) Examples of images for ATF3 and CD68 (F) or ATF3 and CSF1R (G) coimmunofluorescence in breast carcinoma samples. Red, ATF3; green, CD68 or CSF1R; blue, Topro-3 (nuclei). Arrowheads indicate cells with ATF3 expression; arrows indicate those without. Dashed lines demarcate cell boundaries. Scale bars: 100 μm (C, E, and F and G, left); 5 μm (F and G, right). *P < 0.05, log-rank test.