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

Abstract

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 basallike 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 signal transducer and activator of transcription 3 (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 triplenegative 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 TNBC and that combination treatment with STAT3 and GR inhibitors could provide synergistic therapeutic efficacy. Research.

Activated STAT3 Is a Novel Regulator of the XRCC1 Promoter and Selectively Increases XRCC1 Protein Levels in Triple Negative Breast Cancer

“…As a result, we see overexpression of STAT3 being sufficient to drive XRCC1 expression in MDA-231 cells ( Figure 4 ), as well as stimulation by IL-6 and EGF ( Figure 7 and Supplementary Materials Figure S5 ). These results are consistent with two recent studies, which examined the role STAT3 plays in regulating growth and invasion in TNBC cell lines [ 51 , 52 ]. Both studies used CHiP-seq to examine the transcriptional regulation of genes by STAT3.…”

“…While their focus was on proliferation, migration and invasion genes, examination of the CHiP-seq results (GSE85579 and GSE152203) at the XRCC1 promoter showed STAT3 binding sites within the MDA-MB-231, MDA-MB-468, and HCC70 cells [ 51 , 52 ]. These CHiP-seq results in basal-like TNBC cell lines support our findings of higher expression and activation of STAT3 resulting in increased XRCC1 expression [ 11 , 51 , 52 ]. Further validation of the pSTAT3 dependence of these sites is needed to better understand the impact of the conditional regulation of XRCC1 by pSTAT3 in TNBC.…”

Genome-wide crosstalk between steroid receptors in breast and prostate cancers

“…GR and ER also undergo a crosstalk with a TF signal transducer and activator of transcription 3 (STAT3) that becomes activated after phosphorylation in response to interferons, EGF, interleukin (IL-)5 and IL-6. For example, in basal-like TNBC cells, GR operates with STAT3 in a genome-wide manner to drive BCa growth ( Conway et al 2020 ). Since the activation of STAT3 reprograms binding of ER on enhancers and induces metastasis of ER+ BCa ( Siersbæk et al 2020 ), it could act as a central TF, defining the tumor-inducing or repressing role of the SR.…”

“…Thus, a more viable option to treat TNBC or GR-induced ENZ-resistant PCa would be to inhibit the action of the GR through other signaling pathways, while retaining the beneficial systemic effect of glucocorticoids. In ENZ-resistant PCa, these kinds of pathways could be BET ( Shah et al 2017 ) or PI3K/AKT ( Adelaiye-Ogala et al 2020 ), whereas in TNBC, STAT3 ( Conway et al 2020 ) or p38 MAPK ( Perez Kerkvliet et al 2020 ) could be targeted. Future investigations will determine if sufficient attenuation of GR signaling can be obtained through these pathways or if other yet to be discovered pathways will be more effective.…”

A guide to changing paradigms of glucocorticoid receptor function—a model system for genome regulation and physiology

“…For example, luminal breast cancer is usually driven by the activity of estrogen receptor alpha. The more aggressive so-called triple negative basal-like breast cancers that lacks estrogen receptor alpha shows that GR and STAT3 bind to the same regions in the DNA of this cancer type at unmethylated DNA regions [101]. This suggests that inhibition of the combined GR/STAT3 signalling in this difficult-to-treat cancer could serve as a novel concept for therapy.…”