Effects of tumor stroma interaction on global gene expression in breast cancer

Abstract

10006 Background: Perturbations in cell-cell interaction are a key feature of cancer. However, the systematic effects of cell-cell interaction on global gene expression in cancer are largely unexplored. We hypothesized that gene expression signatures induced by cell-cell interaction might be of clinical relevance. Methods: We simulated tumor-stroma interaction in vitro by systematically co-cultivating each of 7 different breast cancer cell lines with stromal fibroblasts from 3 different sites, and determined associated gene expression changes with cDNA microarrays. A dataset of pretreatment gene expression profiles from 295 early stage breast cancers (stage 1 and 2) with a median follow up of 12.6 years allowed us to evaluate the prognostic significance of the gene expression signatures of specific cell-cell interactions derived from our ex vivo models. Results: The most prominent response to epithelial-mesenchymal interaction was an induction of interferon-response genes (IRG), observed in 4 of the 7 breast cancer cell lines in co-culture with fibroblasts, but not in normal mammary epithelial cells. In response to close contact with these breast cancer cells, the fibroblasts secreted type I interferons, which, in turn, induced expression of the IRG in the tumor cells. Immunohistochemical analysis of human breast cancer tissues showed that Stat1, the key transcriptional activator of the IRG, and itself an IRG, was expressed in a subset of the cancers, with a striking pattern of elevated expression in the cancer cells in contact with, or close proximity to, the tumor stroma - paralleling the response seen in our ex vivo model. In vivo, expression of the IRGs was remarkably coherent, providing a basis for segregation of the 295 early-stage breast cancers into two groups by unsupervised hierarchical clustering with the IRG. Tumors with high expression levels (n=161) of IRG were associated with significantly shorter overall survival; 59% at 10 years versus 80% at 10 years for tumors with low expression levels (n=134) (log-rank p=0.001). Conclusions: Our results suggest that an interaction between some breast cancer cells and stromal fibroblasts can induce an interferon response, and that this response may be associated with a greater propensity for tumor progression. No significant financial relationships to disclose.