Tumor metastasis, the leading cause of cancer deaths, is a multistep process with a few key steps believed to be rate limiting. The final step of metastasis, the growth of tumor cells at distal sites, is one key step. Both experimental and clinical data suggest that dispersed tumor cells can remain dormant for many years before developing into malignant tumors. However, little is known about how the growth of such metastatic cells is regulated. This switch from dormancy to malignancy could be attributed to manipulation of tumor cell behavior by the adjoining stromal cells. In this study we have demonstrated an Ets2-specific mechanism in tumor associated macrophages (TAMs) involved in promoting aggressive metastatic growth.

Elevated expression of Ets2, a member of the Ets family of transcription factors, has been correlated with breast cancer, putatively by its activity in the stroma. It is also an important effector molecule in the CSF-1 mediated pro-inflammatory pathway in macrophages. Additionally, Ets2 activates or represses transcription of target genes in a context dependent manner.

Mouse modeling results described here demonstrate that Ets2 activity in TAMs creates a favorable angiogenic environment, in part, by repressing a set of genes that negatively regulate angiogenesis, resulting in metastatic growth. We also observe similar Ets2-dependent molecular changes in the immature myeloid precursors in bone marrow of tumor-bearing mice. Thus, this Ets2-mediated program is involved in ‘educating’ myeloid cells even before their physical association with tumor cells.

The mouse Ets2-TAM signature could also distinguish between lymphocyte/leukocyte infiltration positive and negative human breast tumor samples. A subset of this profile was sufficient to retrospectively predict disease free survival among breast cancer patients. Interestingly, the Ets2-TAM signature stratified estrogen receptor negative patient samples into two distinct survival groups, in contrast to other existing mammary tumor gene signatures developed to predict patient survival. Our approach uncovered molecular mechanisms that regulate metastatic tumor growth and identified potential stromal biomarkers for human breast tumor metastasis.