STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation

Abstract

Breast cancers can be divided into subtypes with different prognoses and treatment responses based on global gene expression differences. Luminal breast cancer gene expression and proliferation are driven by the transcription factors Estrogen Receptor a (ER), FOXA1 and GATA3. Targeting ER is the most effective therapy for treating luminal breast cancer because ER is the master regulator of the luminal gene expression program.In contrast, it is unclear which transcription factors are responsible for driving the gene expression signature that defines basal-like triple negative breast cancer, and there are no targeted therapies approved to treat this aggressive subtype of the disease. This study utilized integrated analysis of DNA methylation, chromatin accessibility, transcription factor binding, and gene expression in large collections of breast cancer cell lines and patient tumors to identify transcription factors responsible for the basal-like gene expression program. The results of this study indicate that glucocorticoid receptor (GR) and signal transducer and activator of transcription 3 (STAT3) bind to the same genomic regulatory regions that are specifically open and unmethylated in basal-like breast cancer. These transcription factors cooperate to regulate expression of hundreds of genes in the basallike gene expression signature and these downstream genes are associated with poor prognosis in patients.Furthermore, combination treatment with small molecule drugs that inhibit both transcription factors leads to synergistic decreases in cell proliferation in cell lines and patient-derived organoid models. This study demonstrates that GR and STAT3 cooperate to regulate the basal-like breast cancer gene expression program and provides the basis for improved therapy for basal-like triple negative breast cancer through rational combination of STAT3 and GR inhibitors.) in the chromatin regions that were specifically open in basal-like tumors and closed in luminal tumors ( Figure 1E). While the enrichment for the GR motif is significant, it is lower than that of STAT3 and JUN/AP1, which is consistent with previous studies that suggest GR can be tethered to some enhancers through protein:protein interactions, rather than direct DNA binding(30). MEC, JMM, JMG, KPG, PGO, and SLP performed experiments. MEC and KEV performed analysis and wrote the manuscript. PY and JT provided reagents. DJB, BEW, and RMM provided expertise and feedback.