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 2

Atf3 deficiency in the host reduces metastasis, but not primary tumor growth.

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Atf3 deficiency in the host reduces metastasis, but not primary tumor g...
(A) Orthotopic injection model in C57BL/6 mice. (B) Primary tumors from WT (Atf3+/+; n = 16) or KO (Atf3–/–; n = 14) mice injected with PyMT cells were measured. A representative result from 3 experiments is shown. P = NS, Mann-Whitney test. (C) Lung nodules at day 85 were analyzed for percent mice that developed lung metastases. Numbers above bars indicate metastasis incidence. *P < 0.05, χ2 test. (D) Lung nodules at day 85 were analyzed for numbers of lung nodules per mouse. *P < 0.05, Student’s t test. (E) Lung nodules at day 85 were analyzed for lung burden per mouse (as rank orders; WT n = 16, KO n = 14). *P < 0.05, Mann-Whitney test. (F) Representative images of lungs at day 85. Arrows indicate metastases. (G) Orthotopic injection model in FVB/N mice. (H) Primary tumors from WT or KO mice injected with MVT-1 cells were analyzed as in B. A representative result from 2 experiments is shown (n = 5). P = NS, Mann-Whitney test. (I) Mice from H at day 35 were analyzed as in C for percent developed lung metastases. *P < 0.01, χ2 test. (J) Mice from H at day 35 were analyzed for lung nodule numbers per mouse (n = 11). *P < 0.001, Mann-Whitney test. (K) Representative images at day 35. Arrows indicate metastases.