Tumor Macrophages Utilize Atf3 To Promote Breast Cancer Metastasis

Objective: Cancer progression is facilitated by a complex network of interactions between cancer cells and host-derived components, such as stromal cells and extracellular matrix in the tumor microenvironment. We sought to identify the factors that mediate these dynamic cancer-host interplays. Specifically, we asked how the host responds to signals from the cancer cells. To this end, we investigated the role of ATF3, an adaptive-response gene in the cellular stress response network. Overwhelming evidence indicates that ATF3 is induced by a broad spectrum of extra- and intra-cellular signals in a variety of cell types. As such, it is as an excellent candidate for mediating host responses to cancer cells. Methods: We injected breast cancer cells (MMTV-PyMT cells) into syngeneic wild type (WT) or ATF3 knockout (KO) mice, performed survival surgery to remove the primary tumors, and examined metastasis two months after tumor removal. Results: We found that ATF3 deficiency in the host did not affect primary tumor formation; excitingly, though, it dramatically decreased lung metastasis. Analyses of the circulating tumor cells and lung colonization indicated that both early and late steps in the metastatic cascade were defective in the KO host. Since soluble factors are an integral part of the mechanisms by which the host transmits systemic responses, we analyzed the plasma of normal and tumor-bearing mice by an antibody array. Intriguingly, plasma from tumor-bearing KO mice demonstrated a marked impairment in the abundance of various molecules that are known to play important roles in metastasis, suggesting that ATF3 in the host promotes a systemic environment that enhances cancer metastasis. Since the KO mice are whole body KO, the results above do not indicate the cell type(s) in which ATF3 is playing this critical role. We will present evidence that ATF3 plays an important role, at least in part, in the tumor associated macrophages (TAMs), where it up-regulates MMP9 as a functionally important target gene. Two lines of evidence indicated that our findings on ATF3 have clinical relevance. First, analyses of human tumor microarrays by immunohistochemistry revealed that ATF3 expression in monocytic cells correlated with poor outcome. Second, analyses of the mouse TAMs from the WT and KO host identified ∼400 ATF3-regulated genes. Among these genes, a 60-gene signature was identified that could distinguish the human breast tumor stroma from the normal breast stroma (McGill Breast Stroma dataset). Significantly, this signature predicted outcome in two independent patient cohorts. Conclusion and Significance: We uncovered a previously unknown role for ATF3: it is induced in the host during cancer development and its expression in the host cells, specifically the TAMs, promotes metastasis. This finding is significant because it not only links host stress response to cancer metastasis, it also identified a new gene signature that predicts outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2843. doi:10.1158/1538-7445.AM2011-2843