Transcription factor ATF3 links host adaptive response to breast cancer metastasis.
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.
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA.
Chris C
CC
Wolford
Stephen J
SJ
McConoughey
Swati P
SP
Jalgaonkar
Marino
M
Leon
Anand S
AS
Merchant
Johnna L
JL
Dominick
Xin
X
Yin
Yiseok
Y
Chang
Erik J
EJ
Zmuda
Sandra A
SA
O'Toole
Ewan K A
EK
Millar
Stephanie L
SL
Roller
Charles L
CL
Shapiro
Michael C
MC
Ostrowski
Robert L
RL
Sutherland
Tsonwin
T
Hai
D051700:Activating Transcription Factor 3 / Q000502:physiology*; D056704:Adaptive Immunity; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002465:Cell Movement; D018920:Coculture Techniques; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015999:Multivariate Analysis; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis; D059467:Transcriptome; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D012333:RNA, Messenger; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9