Introduction: Runx1 belongs to the Runx family of transcription factors. Translocation of Runx1 is well established as a causative factor of leukemia. However the recognition of Runx1 expression in epithelial lining cells of glands suggests that Runx1 functions in maintaining the integrity of that cell layer. Recent studies have identified Runx1 as one of the top genes mutated in breast cancers. Further Runx1 levels are decreased in high-grade primary breast tumors compared to low/mid-grade tumors. Based on these findings, we raise the hypothesis that Runx1 is a tumor suppressor that functions to maintain the normal epithelial phenotype and that loss of Runx1 could promote epithelial to mesenchymal (EMT). Methods and results: We used two human breast cancer cell models systems, the MCF10A to MCF7/T47D and to MDA-MB-231 and the MCF10A progression model from normal-like mammary epithelial cells (MCF10A) to tumorigenic (MCF10AT1) and to metastatic (MCF10CA1a) cells. We observed that the level of Runx1 is decreased in tumorigenic cells. To understand Runx1 function, Runx1 was depleted by shRNA in mammary epithelial cells that resulting in disrupted/altered cellular morphology and suppressed expression of the epithelial gene E-cadherin. To reinforce this observation, EMT was induced by addition of TGFB1 or by growth factor depletion in MCF10A cells. A striking Runx1 decrease resulted suggesting that Runx1 has a crucial role in preventing EMT. Furthermore our analysis of breast tumors and survival data supports the above finding that loss of Runx1 promotes tumor progression.
Conclusion and Impact: Our results highlight an essential role for Runx1 in maintaining normal epithelial phenotype and preventing epithelial to mesenchymal transition as well as tumor progression in breast cancer. Identifying this Runx1 mechanism provides the basis for a novel strategy to treat early stage breast cancer.
Citation Format: Deli Hong, Terri Messier, Andrew Fritz, Gillian Browne, Janet Stein, Jane Lian, Gary Stein. Runx1 is obligatory for mammary epithelial cell morphology and phenotype. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1178.