INVESTIGATION OF TGF-??ASSOCIATED MASTER-LIKE TRANSCRIPTION FACTORS IN BREAST CANCER

Abstract

Transforming growth factor β (TGF-β) signaling is important in early development, lineage specification, and tumorigenesis. In cancer, TGF-β can function as either a tumor suppressor or a tumor promoter at different stages of carcinogenesis. In early development, the context specificity of TGF-β signaling is partially determined by master transcription factors guiding SMAD-dependent genomic regulation. We hypothesize that a similar role for “master-like transcription factors” may determine context-specific genomic regulation of TGF-β signaling in tumorigenesis. We address this problem through integrative genomic studies and bioinformatics analysis of TGF-β-responsive breast cancer cell models, as well as data from TCGA. We identify a context-specific interaction between E2F Transcription Factor 1 (E2F1) and SMAD-dependent signaling in MCF7, an ER-positive luminal-A breast cancer model. E2F1 is a potential master-like transcription factor in this setting: it is not required for SMAD3 binding, but co-occupies genomic sites with SMAD3 and coordinates with SMAD3 to regulate downstream genes. Moreover, 138 putative super-enhancers were found in response to TGF-β in MCF7, whose associated genes were enriched in ten oncogenic gene sets including RB-mediated oncogenes and TGF-β mediated oncogenes.