Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition
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Deli Hong1,2, Terri L. Messier1, Coralee E. Tye1, Jason R. Dobson2, Andrew J. Fritz1, Kenneth R. Sikora1, Gillian Browne1, Janet L. Stein1, Jane B. Lian1, Gary S. Stein1
1Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA
2Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA
Gary S. Stein, email: email@example.com
Keywords: Runx1, epithelial to mesenchymal transition, epithelial Integrity, patient survival, breast cancer
Received: November 17, 2016 Accepted: January 16, 2017 Published: February 16, 2017
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.
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