STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation
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ABSTRACT:
PROVIDER: PRJNA638631 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11977370.fastq.gz | Fastqsanger.gz | |||
| SRR11977371.fastq.gz | Fastqsanger.gz | |||
| SRR11977372.fastq.gz | Fastqsanger.gz | |||
| SRR11977373.fastq.gz | Fastqsanger.gz | |||
| SRR11977374.fastq.gz | Fastqsanger.gz |
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Project description:Breast cancers can be divided into subtypes with different prognoses and treatment responses based on global gene expression differences. 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.
2020-06-11 | GSE152203 | GEO
Project description:Transcription factor recruitment to genomic sites of action is primarily due to direct protein:DNA interactions. The subsequent recruitment of co-regulatory complexes leads to either transcriptional activation or repression. In contrast to this canonical scheme, some transcription factors such as the glucocorticoid receptor (GR) behave as transcriptional repressors when recruited to target genes through protein tethering. We have investigated the genome-wide prevalence of tethering between GR and Stat3 and found non-reciprocal interactions, namely that GR tethering to DNA-bound Stat3 results in transcriptional repression whereas Stat3 tethering to GR results in synergism. Further, other schemes of GR and Stat3 co-recruitment to regulatory modules result in transcriptional synergism, including neighbouring and composite binding sites. The results indicate extensive transcriptional interactions between Stat3 and GR; further, they provide a genome-wide assessment of transcriptional regulation by tethering and a molecular basis for integration of signals mediated by GR and Stats in health and disease. ChIP-seq analysis of Stat3 and GR binding sites in pituitary corticotroph AtT-20 cell model. Five independant ChIPs were pooled prior library preparation for each contitions: STAT3 (LIF), STAT3 (Dex+LIF), GR (Dex+LIF), GR (Dex) and control IgG.
2012-06-06 | E-GEOD-37235 | biostudies-arrayexpress
Project description:Transcription factor recruitment to genomic sites of action is primarily due to direct protein:DNA interactions. The subsequent recruitment of co-regulatory complexes leads to either transcriptional activation or repression. In contrast to this canonical scheme, some transcription factors such as the glucocorticoid receptor (GR) behave as transcriptional repressors when recruited to target genes through protein tethering. We have investigated the genome-wide prevalence of tethering between GR and Stat3 and found non-reciprocal interactions, namely that GR tethering to DNA-bound Stat3 results in transcriptional repression whereas Stat3 tethering to GR results in synergism. Further, other schemes of GR and Stat3 co-recruitment to regulatory modules result in transcriptional synergism, including neighbouring and composite binding sites. The results indicate extensive transcriptional interactions between Stat3 and GR; further, they provide a genome-wide assessment of transcriptional regulation by tethering and a molecular basis for integration of signals mediated by GR and Stats in health and disease.
2012-06-07 | GSE37235 | GEO
Project description:Breast cancers can be divided into subtypes with different prognoses and treatment responses based on global gene expression differences. 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.
2020-06-11 | GSE152201 | GEO
Project description:Breast cancer is a heterogeneous disease comprised of four molecular subtypes defined by whether the tumor-originating cells are luminal or basal epithelial cells. Breast cancers arising from the luminal mammary duct often express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2). Tumors expressing ER and/or PR are treated with anti-hormonal therapies, while tumors overexpressing HER2 are targeted with monoclonal antibodies. Immunohistochemical detection of ER, PR, and HER2 receptors/proteins is a critical step in breast cancer diagnosis and guided treatment. Breast tumors that do not express these proteins are known as “triple negative breast cancer” (TNBC) and are typically basal-like. TNBCs are the most aggressive subtype, with the highest mortality rates and no targeted therapy, so there is a pressing need to identify important TNBC tumor regulators. The signal transducer and activator of transcription 3 (STAT3) transcription factor has been previously implicated as a constitutively active oncogene in TNBC. However, its direct regulatory gene targets and tumorigenic properties have not been well characterized. By integrating RNA-seq and ChIP-seq data from 2 TNBC tumors and 4 cell lines, we discovered novel gene signatures directly regulated by STAT3 that were enriched for processes involving inflammation, immunity, and invasion in TNBC. Functional analysis revealed that STAT3 has a key role regulating invasion and metastasis, a characteristic often associated with TNBC. Our findings suggest therapies targeting STAT3 may be important for preventing TNBC metastasis.
2017-06-10 | GSE85579 | GEO
Project description:Triple-negative (TN) and Basal-like (BL) breast cancer definitions have been used interchangeably to identify breast cancers that lack expression of the hormonal receptors (HR) and overexpression and/or amplification of HER2. However, both classifications when compared to each other, show substantial discordance rates. Here, we molecularly characterize TN tumors, and Basal-like tumors, and compare and contrast the results in terms of common patterns and distinct patterns for each. In total, when testing 412 TN and 473 Basal-like tumors, 21.4% and 31.5% were identified as non-Basal-like and non-TN, respectively. TN tumors identified as Luminal or HER2-enriched showed undistinguishable overall gene expression profiles when compared versus Luminal or HER2-enriched tumors that were not TN. Similar findings were observed within Basal-like tumors regardless of the TN status. Interestingly, most TN tumors identified as HER2-enriched showed low HER2 expression and lack of HER2 amplification despite the similar overall gene expression profiles to HER2-E tumors that were not TN. Lastly, additional genomic classifications are examined within TN and Basal-like cancers, most of which are largely concordant with tumor intrinsic subtype. These results suggest that future clinical trials focused on TN disease should consider stratifying patients based on Basal-like versus non-Basal-like gene expression profiles as this appears to be the main biological difference seen within TN breast cancer patients. reference x sample
2014-07-29 | E-GEOD-41119 | biostudies-arrayexpress
Project description:To determine how the transcription factors GR and STAT3 cooperate to regulate gene expression, the MDA-MB-231 breast cancer cell line was treated with dexamethasone (1µM for 24 hours) and the STAT3 inhibitor SH4-54 (8µM for 24 hours) alone and in combination. A multivariate linear model with a GR:STAT3 interaction term was used to identify genes that are differentially expressed when both TFs are fully active in the nucleus.
2020-08-21 | GSE137535 | GEO
Project description:Triple-negative (TN) and Basal-like (BL) breast cancer definitions have been used interchangeably to identify breast cancers that lack expression of the hormonal receptors (HR) and overexpression and/or amplification of HER2. However, both classifications when compared to each other, show substantial discordance rates. Here, we molecularly characterize TN tumors, and Basal-like tumors, and compare and contrast the results in terms of common patterns and distinct patterns for each. In total, when testing 412 TN and 473 Basal-like tumors, 21.4% and 31.5% were identified as non-Basal-like and non-TN, respectively. TN tumors identified as Luminal or HER2-enriched showed undistinguishable overall gene expression profiles when compared versus Luminal or HER2-enriched tumors that were not TN. Similar findings were observed within Basal-like tumors regardless of the TN status. Interestingly, most TN tumors identified as HER2-enriched showed low HER2 expression and lack of HER2 amplification despite the similar overall gene expression profiles to HER2-E tumors that were not TN. Lastly, additional genomic classifications are examined within TN and Basal-like cancers, most of which are largely concordant with tumor intrinsic subtype. These results suggest that future clinical trials focused on TN disease should consider stratifying patients based on Basal-like versus non-Basal-like gene expression profiles as this appears to be the main biological difference seen within TN breast cancer patients.
2014-07-29 | GSE41119 | GEO
Project description:Breast tumors are highly heterogeneous and for many molecular subtypes no targeted therapies are available. These include breast cancers that display hallmarks of epithelial to mesenchymal transition (EMT), a process related to metastasis and enriched in triple negative breast cancers (TNBCs). To determine whether this EMT cellular state could be therapeutically exploited, we performed a large-scale chemical genetic screen. We identified a group of structurally related compounds, including the clinically advanced drug PKC412 (midostaurin), that targeted post-EMT breast cancer cells. PKC412 induced apoptosis specifically in basal-like TNBC cells and inhibited tumor growth in vivo. Structure activity relationship (SAR) studies, chemical proteomics, and computational modeling identified the kinase SYK as a critical PKC412 target. Specific SYK inhibitors and PKC412 displayed a similar profile across a large panel of breast cancer cell lines, indicating a shared mode of action. Phosphoproteomics analysis revealed that SYK activates STAT3, and chemical or genetic inhibition of STAT3 resulted in cell death in basal-like breast cancer cells. This non-oncogene addiction of basal-like breast cancer cells to SYK suggests that chemical SYK inhibition may be beneficial for a specific subset of triple negative breast cancer patients.
2016-06-15 | PXD001680 | Pride
Project description:Dimerization is believed necessary for receptor tyrosine kinases (RTKs) activation. Here we report that monomeric epidermal growth factor receptor (EGFR) directly phosphorylates the signal transducer and activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25 (hereafter referred to as TAMER (Transmembrane protein Antagonizing Monomeric EGF Receptor signaling) to reflect its molecular function). We identified TAMER as a checkpoint for the monomeric-EGFR/STAT3 signaling, and downregulation of TAMER in triple-negative breast cancer (TNBC) results in a persistent activation of STAT3 that is required for TNBC progression, which gives a good explanation why targeting EGFR dimerization by antibodies showed no significant benefit to TNBC patients in clinical trials. Remarkably, supply of TAMER strongly suppressed TNBC progression, presenting a promising targeted therapy for TNBC. Hence, our study demonstrated the first RTK monomer-mediated signaling pathway, introducing an unprecedented pattern of RTK signaling that may play key roles in certain physiological or pathological contexts, which might need to be inspected for therapeutically targeting RTKs in the future.In this paper, RNA-seq were used to identify different gene expression in WT and TMEM25 knockout MDA-MB-231 cells.
2024-07-28 | GSE180989 | GEO