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.

Transcription factor ATF3 mediates the radioresistance of breast cancer

“…On the contrary, if ATF3 expression in breast cancer cells was silenced by the siATF3 transfection or was suppressed by the signalling pathway inhibitor LY204002, breast cancer radioresistance could be relieved to a great extent and the radiation therapy efficiency can be also improved. Overwhelming evidence showed that ATF3 was highly expressed and was closely related to cell migration in breast cancer 6, 18. Gokulnath et al found that silencing of ATF3 expression could also decrease the production of MMP‐13 and Runx2 genes related to invasive and metastatic 18.…”

“…Overpowering evidence proved that ATF3 translated by an immediate early gene and its expression is weak in various cells. But ATF3 expression can be triggered by multiple cellular signals 6. According to existing investigations, ATF3 is supposed to be a crossroad of the cellular response network and ATF3 have been proved to take a place on canceration course of breast epithelial cells 7.…”

A Review of Cancer Immunotherapy and Nutritional Therapies

“…Stress also can indirectly promote cancer by weakening the immune system through releasing high levels of cortisol and epinephrine. Many studies have shown that these hormones make breast, ovarian and prostate cancer cells resistant to destruction [24][25][26].…”

Harnessing the immune system for the treatment of breast cancer

“…TAMs also promote breast cancer cell survival through α4-integrin-dependent binding of macrophage to vascular cell adhesion molecule-1 (VCAM-1)-expressing tumor cells, which favors breast cancer cell metastatic colonization . Wolford et al (2013) showed that induction of the expression of ATF3 and its downstream gene matrix metalloproteinase-9 (MMP-9) in macrophages leads to enhanced breast cancer invasiveness and metastasis. Ishihara et al (2013) revealed that Wiskott-Aldrich syndrome protein (WASp)-mediated EGF shedding by TAMs was required to enhance breast cancer motility, intravasation, and metastasis.…”