An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis.
Tumor-associated macrophages (TAM) are implicated in breast cancer metastasis, but relatively little is known about the underlying genes and pathways that are involved. The transcription factor Ets2 is a direct target of signaling pathways involved in regulating macrophage functions during inflammation. We conditionally deleted Ets in TAMs to determine its function at this level on mouse mammary tumor growth and metastasis. Ets2 deletion in TAMs decreased the frequency and size of lung metastases in three different mouse models of breast cancer metastasis. Expression profiling and chromatin immunoprecipitation assays in isolated TAMs established that Ets2 repressed a gene program that included several well-characterized inhibitors of angiogenesis. Consistent with these results, Ets2 ablation in TAMs led to decreased angiogenesis and decreased growth of tumors. An Ets2-TAM expression signature consisting of 133 genes was identified within human breast cancer expression data which could retrospectively predict overall survival of patients with breast cancer in two independent data sets. In summary, we identified Ets2 as a central driver of a transcriptional program in TAMs that acts to promote lung metastasis of breast tumors.
Department of Molecular and Cellular Biochemistry, Center for Biostatistics, College of Public Health, and Tumor Microenvironment Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.
Tahera
T
Zabuawala
David A
DA
Taffany
Sudarshana M
SM
Sharma
Anand
A
Merchant
Brett
B
Adair
Ruchika
R
Srinivasan
Thomas J
TJ
Rosol
Soledad
S
Fernandez
Kun
K
Huang
Gustavo
G
Leone
Michael C
MC
Ostrowski
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000502:physiology*; D012189:Retrospective Studies; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; C494070:Ets2 protein, mouse; D050787:Proto-Oncogene Protein c-ets-2