RT Journal Article
SR Electronic
T1 STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 730606
DO 10.1101/730606
A1 Megan E. Conway
A1 Joy M. McDaniel
A1 James M. Graham
A1 Katrin P. Guillen
A1 Patsy G. Oliver
A1 Stephanie L. Parker
A1 Peibin Yue
A1 James Turkson
A1 Donald J. Buchsbaum
A1 Bryan E. Welm
A1 Richard M. Myers
A1 Katherine E. Varley
YR 2019
UL http://biorxiv.org/content/early/2019/08/09/730606.abstract
AB 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 α (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 basal-like 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.