Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition

Abstract

Runx1 is a well characterized transcription factor essential for hematopoietic differentiation and Runx1 mutations are the cause of leukemias. Runx1 is highly expressed in normal epithelium of most glands and recently has been associated with solid tumors. Notably, the function of Runx1 in the mammary gland and how it is involved in initiation and progression of breast cancer is still unclear. Here we demonstrate the consequences of Runx1 loss in normal mammary epithelial and breast cancer cells. We first observed that Runx1 is decreased in tumorigenic and metastatic breast cancer cells. We also observed loss of Runx1 expression upon induction of epithelial-mesenchymal transition (EMT) in MCF10A (normal-like) cells. Furthermore depletion of Runx1 in MCF10A cells resulted in striking changes in cell shape, leading to mesenchymal cell morphology. The epithelial phenotype could be restored in breast cancer cells by re-expressing Runx1. Analyses of breast tumors and patient data revealed that low Runx1 expression is associated with poor prognosis and decreased survival. We addressed mechanisms for the function of Runx1 in maintaining the epithelial phenotype and find Runx1 directly regulates E-cadherin; and serves as a downstream transcription factor mediating TGFβ signaling. We also observed through global gene expression profiling of growth factor depleted cells that induction of EMT and loss of Runx1 is associated with activation of TGFβ and WNT pathways. Thus these findings have identified a novel function for Runx1 in sustaining normal epithelial morphology and preventing EMT and suggest Runx1 levels could be a prognostic indicator of tumor progression.

Identification of tRNA‐derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer

“…Our previous studies present compelling evidence that RUNX1 expression in mammary cells and inhibits tumorigenic potential supporting maintenance of an epithelial‐like phenotype; RUNX1 protein and mRNA expression are reduced in breast cancer cell lines (Hong, Fritz, Finstad et al, ; Hong et al, ). The expression of candidate RUNX1‐responsive tsRNA, ts‐19, ts‐29, ts‐46, and ts‐112, was curated from our initial microarray study (Balatti et al, ) and plotted to discover dynamic regulation in breast cancer cell models (Figure a–d).…”

“…RUNX1 was inhibited in MCF10A cells or overexpressed in MCF10CA1a cells as previously described (Hong, Fritz, Finstad et al, ; Hong et al, ).…”

“…Expression of RUNX1 has been shown to maintain the mammary epithelium, as loss of RUNX1 in normal‐like mammary epithelial cells promoted mesenchymal gene expression and repressed epithelial genes. Thus, the epithelial‐to‐mesenchymal transition was suppressed by RUNX1 (Hong, Fritz, Zaidi et al, ; Hong et al, ). Furthermore, ectopic overexpression of RUNX1 in aggressive breast cancer cells reduced migration, invasion, and stemness, as well as inhibited tumor growth in mice as determined by reduced xenograft size in the mammary fat pad (Hong, Fritz, Finstad et al, ).…”

RUNX1, a new regulator of EMT in breast cancer

“…Therefore, molecular characterization of EMT modulators could be a significant step toward better understanding and restraining of metastasis. In this issue, Hong and colleagues demonstrate a novel function of RUNX1 in sustaining mammary normal epithelial morphology and preventing EMT, and suggest that RUNX1 levels could be a prognostic indicator of breast cancer progression [3]. …”

“…In their latest study, Hong and coworkers identified a novel role of Runx1 in regulating breast cancer progression [3]. Initially, authors demonstrated that Runx1 expression is reduced in a number of breast cancer cell lines.…”