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 7

ATF3 facilitates the ability of macrophages to enhance breast cancer cell transendothelial migration.

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ATF3 facilitates the ability of macrophages to enhance breast cancer cel...
(A) Transendothelial migration assay using Boyden chamber. C.M., conditioned media. (B) MVT-1 cells labeled with tGFP were placed on top of a monolayer of HUVECs, without (–) or with WT or KO bone marrow–derived macrophages in the bottom chamber. Alternatively, conditioned media from macrophages transduced with control, ATF3-expressing, or Mmp9-expressing retrovirus were placed in the bottom chamber. tGFP cells on the underside of the membrane were counted (see Supplemental Methods), and the number in the absence of macrophages was defined as 1. A representative result from 3 experiments is shown. *P < 0.05, Student’s t test. (C) Representative images of conditioned media from virus-transduced macrophages in B. (D) WT or KO FVB/N mice were injected with tGFP-labeled MVT-1 cancer cells by tail vein; lung sections were analyzed for tGFP+ cells at the indicated hours after injection (n = 3 per group). *P < 0.05, Student’s t test. (E) Representative images of samples from D. Scale bars: 100 μm (C); 50 μm (E).