Tumor resident stromal cells promote breast cancer invasion through regulation of the basal phenotype

Abstract

Collective invasion can be led by breast cancer cells expressing basal epithelial markers, typified by keratin-14 (KRT14). We analyzed gene expression data from The Cancer Genome Atlas and demonstrated a significant correlation between a KRT14+ invasion signature and a stromal mediated extracellular matrix (ECM) organization module. We then developed a novel co-culture model of tumor organoids with autologous stromal cells. Co-culture significantly increased KRT14 expression and invasion of organoids from both luminal and basal murine breast cancer models. However, stromal cell conditioned medium induced invasion but not KRT14 expression. Cancer cells released TGF-β and that signaling pathway was required for stromal cell-induced invasion and KRT14 expression. Mechanistically, TGF-β induced NOX4 expression in stromal cells and NOX4 inhibition reduced invasion and KRT14 expression. In summary, we developed a novel co-culture model and revealed dynamic molecular interactions between stromal cells and cancer cells that regulate both basal gene expression and invasive behavior. Implications: Fibroblasts within mammary tumors can regulate the molecular phenotype and invasive behavior of breast cancer cells.