Transcription factor ATF3 links host adaptive response to breast cancer metastasis
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
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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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 3

Atf3 deficiency in the host impairs both early and late events in metastasis.

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Atf3 deficiency in the host impairs both early and late events in metas...
(A) WT and KO C57BL/6 mice were injected with PyMT cells at mammary fat pad. 25 days later, blood cells were isolated and analyzed by RT-qPCR for PyMT as an indicator for CTCs. Blood cells from WT mice with no PyMT cell injection were used as a control. Signals were standardized against tubulin, and the standardized signal from the control mice was arbitrarily defined as 1. A representative result from 2 experiments is shown (n indicated above bars). *P < 0.05, Mann-Whitney test. (B) WT (n = 10) and KO (n = 7) C57BL/6 mice were injected with PyMT cancer cells by tail vein, and lung nodules per mouse were counted at 90 days after injection. A representative result from 3 experiments is shown. Data are expressed as nodule area (pixels) per lung (pixels). *P < 0.05, Mann-Whitney test. (C) Representative images of lungs from B. (D) Same as A, except FVB/N mice injected with MVT-1 cells were analyzed at day 35 for cMyc. A representative result from 2 experiments is shown. *P < 0.05, Mann-Whitney test. (E) Same as B, except FVB/N mice injected with MVT-1 cells were analyzed at day 18 for lung nodule area using NIH ImageJ. A representative result from 3 experiments is shown (n = 10). *P < 0.001, Mann-Whitney test. (F) Representative images of H&E stain of lungs from E.