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 4

ATF3 is functionally important in macrophage/myeloid cells.

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ATF3 is functionally important in macrophage/myeloid cells. (A) WT C57BL...
(A) WT C57BL/6 mice transplanted with WT or KO bone marrow–derived cells were injected with PyMT cancer cells and analyzed as in Figure 3E (n = 5). *P < 0.01, Mann-Whitney test; from 1 of 2 experiments. (B) Representative images of lungs from A. (C) Engraftment was assessed by analyzing blood cells for Atf3 using RT-qPCR. Standardized signals (against tubulin) from WT transplantation were defined as 1 (n = 5). *P < 0.05, Mann-Whitney test. (D) Atf3 flox allele (Atf3f). (E) Peritoneal macrophages (MΦ) from CKO (Atf3f/f/LysM-Cre) or control (Atf3+/+/LysM-Cre) mice were analyzed. Left: Genomic DNA by PCR for the indicated alleles (F, floxed; R, recombined; W, WT). Reference (Ref.) lane shows the position of the PCR products for the WT and floxed alleles on the same gel. Right: Protein extract by immunoblot. (F) CKO and control mice were injected with MVT-1 cells at fat pads, and their primary tumors were measured (n = 9). From 1 of 3 experiments. (G) Lung nodules from F were counted at day 35. *P < 0.05, Mann-Whitney test. (H) Same as G, except tail vein injection. *P < 0.01, Mann-Whitney test.