STAT3 and GR Cooperate to Drive Gene Expression and Growth of Basal-Like Triple-Negative Breast Cancer

Breast cancers are divided into subtypes with different prognoses and treatment responses based on global differences in gene expression. Luminal breast cancer gene expression and proliferation are driven by estrogen receptor alpha, and targeting this transcription factor is the most effective therapy for this subtype. By contrast, it remains unclear which transcription factors drive the gene expression signature that defines basal-like triple-negative breast cancer, and there are no targeted therapies approved to treat this aggressive subtype. In this study, we utilized integrated genomic 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. Glucocorticoid receptor (GR) and STAT3 bind to the same genomic regulatory regions, which were specifically open and unmethylated in basal-like breast cancer. These transcription factors cooperated to regulate expression of hundreds of genes in the basal-like gene expression signature, which were associated with poor prognosis. Combination treatment with small-molecule inhibitors of both transcription factors resulted in synergistic decreases in cell growth 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. SIGNIFICANCE: This study demonstrates that GR and STAT3 cooperate to activate the canonical gene expression signature of basal-like triple-negative breast cancer and that combination treatment with STAT3 and GR inhibitors could provide synergistic therapeutic efficacy.