Transcription factor ATF3 links host adaptive response to breast cancer metastasis

Saturday, 07/09/2013  |   Breast Cancer  |  no comments

Wolford CC, McConoughey SJ, Jalgaonkar SP, et al. J Clin Invest. 2013;123(7):2893–2906. doi:10.1172/JCI64410.

Cancers are not simply autonomous masses of cells; they secrete soluble factors to elicit systemic responses from the host, and the host responses, in turn, affect cancer cells (1–6). A key target tissue for cancer cells to modulate the host is the bone marrow, which provides precursor cells for various immune cells and mesenchymal cells (7). These precursor cells can be recruited to the primary tumor site; there, they differentiate and become a part of the tumor stroma or microenvironment — in addition to the resident stromal cells. Stromal cells secrete soluble factors to exert their influence on cancer cells, which in turn secrete factors to influence the stromal cells, forming a loop of stroma-cancer interactions.

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.

This study demonstrated that ATF3 — a hub of the cellular adaptive response network — is induced in both the cancer epithelia and the mononuclear cells in the stroma. Our data support a model whereby ATF3 induction in the mononuclear cells (presumably reflecting a reactive stroma) alters their gene expression and bioactivities, contributing to host-enhanced metastasis. Importantly, this expression of ATF3 predicted poor clinical outcome in a cohort of patients, suggesting that dampening ATF3 expression in the host may be a potential therapeutic approach.

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