Abstract 4462: RUNX1 global binding and gene regulation in mammary epithelial cells revealed novel Runx1 mediated cellular activities

Abstract

Abstract The transcription factor RUNX1 is one of the most frequently mutated genes in breast tumors. However, the role of RUNX1 in the mammary gland is understudied. Previously, our group established that RUNX1 has tumor suppressor activities in both normal mammary epithelial and breast cancer cells, including inhibition of epithelial to mesenchymal transition (EMT), migration, and invasion. To better understand the cellular consequences mediated by RUNX1 loss-of-function in mammary epithelial cells, we performed global gene expression profiling (RNA-seq) in Runx1-depleted MCF10A cells. Upon loss of RUNX1, the expression of 1806 genes was significantly altered (with 2-fold change cutoff). Pathway analysis on these differentially expressed genes revealed that RUNX1 is involved in many cellular activities, including lipid metabolism, cell growth and cell cycle control, which were not previously reported. Consistent with expression profiling results, flow cytometry analysis showed the mitotic population in RUNX1 depleted cells was significantly decreased, indicating RUNX1 is important for proper cell division. To investigate the mechanisms by which RUNX1 controls expression of those differentially expressed genes, RUNX1 genome-wide occupancy analysis (ChIP-seq) was performed in MCF10A cells. We found that although RUNX1 binding is enriched at transcription start sites (TSS), RUNX1 also binds to loci distal to TSSs and multiple other regulatory elements. Therefore, RUNX1 has the capability to utilize multiple mechanisms to control target gene expression. Our results highlight crucial roles for RUNX1 in controlling normal growth of mammary epithelial cells, consistent with its tumor suppressor activities. Loss of RUNX1 leads to improper gene regulation and cell cycle defects, which may contribute to tumor progression in breast cancer. These RUNX1-mediated mechanisms point to novel intervention strategies for early stage breast cancer. Citation Format: Deli Hong, Andrew J. Fritz, Coralee E. Tye, Natalie A. Page, Joseph R. Boyd, Jane B. Lian, Janet L. Stein, Gary S. Stein. RUNX1 global binding and gene regulation in mammary epithelial cells revealed novel Runx1 mediated cellular activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4462.