Oncogenic cell fate decision in breast epithelial cells I: growth factors and mechanisms.

Background: Breast cancer cell heterogeneity and cellular fate are governed by a variety of molecular mechanisms. The LINCS (Library of Integrated Network-based Cellular Signatures) consortium performed multi-omics experiments on normal breast epithelial cells, MCF10a, to deduce temporal mechanisms of regulation and cell state signatures contributing to pro-oncogenic phenotypes. Methods: Normal breast epithelial cells were treated with oncogenic ligands such as EGF, HGF, and OSM, and multi-modal measurements including Reverse phase protein Assay (RPPA), RNA-seq, ATAC-seq, and Cyclic immune-fluorescence (Cyclic-IF) were performed. Result: In our integrated analyses of the data to elucidate mechanisms, contextual functional networks were constructed by integrating protein signaling, transcription factor activity, and gene expression. Phenotypic changes in response to the ligands consisted of cell cycle modifications leading to oncogenic events such as loss of apoptosis and induction of EMT (Epithelial to Mesenchymal Transition). Activation of mTOR was observed with all ligands, which led to the activation of E2F1. Downstream transcriptomic regulation of E2F1 led to an increase in both oncogenic signaling and EMT. Additionally, under OSM treatment, activation of STAT3 facilitated the enhancement of EMT via transcriptomic regulation of JUN and FOS. These findings were further validated using the chromatin changes seen in ATAC-seq and protein localization as seen in Cyclic-IF assay. Conclusion: This analysis provides valuable insights into the mechanisms of transcriptional regulation during oncogenesis in normal breast cells treated with growth factors and can aid in the discovery of novel drug targets and treatments.