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

Deli Hong,Kenneth R. Sikora,Janet L. Stein,Coralee E. Tye,Gary S. Stein,Jane B. Lian,Jason R. Dobson,Gillian Browne,Terri L. Messier,Andrew J. Fritz

doi:10.18632/oncotarget.15381

Deli Hong, Kenneth R. Sikora + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.15381

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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.

Highlights

Evidence is rapidly accruing for the oncogenic and tumor suppressor functions of the Runx family of transcription factors, Runx1, Runx2 and Runx3, which are essential for normal lineage specific development [1, 2]
Together our findings indicate an important role for Runx1 in normal breast epithelial cells and provide evidence for the emerging concept that Runx1 may function as a tumor suppressor [17]
Our study has established a crucial role for Runx1 in maintaining the normal epithelial phenotype

Summary

Introduction

Evidence is rapidly accruing for the oncogenic and tumor suppressor functions of the Runx family of transcription factors, Runx, Runx and Runx, which are essential for normal lineage specific development [1, 2]. In late stage cancer, including breast, prostate and thyroid, abnormal expression of Runx drives metastasis to bone [3,4,5]. Inhibition of Runx in metastatic breast and prostate cancer cells drastically reduces tumor growth and metastasis in vivo [3, 6], revealing Runx function as an oncogene. Recent genetic studies have identified loss-of-function somatic mutations or deletion of Runx in breast cancer patients [10, 11]. These data are consistent with evidence that Runx is reduced in metastasis-prone solid tumors [9]. There is a requirement for understanding Runx1-mediated regulatory mechanism(s) in breast cancer

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