Gene expression profile at single cell level of bone metastases from triple-negative breast cancer in mice.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236558 | GEO | 2025/12/17
REPOSITORIES: GEO
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Project description:Breast cancer is the most common malignancy that develops in women, responsible for the highest cancer-associated death rates. Triple negative breast cancers (TNBC) represent an important subtype that have an aggressive clinical phenotype, are associated with a higher likelihood of metastasis and are not responsive to current targeted therapies. miRNAs have emerged as an attractive candidate for molecular biomarkers and treatment targets in breast cancer, but their role in the progression of TNBC remains largely unexplored. This study has investigated miRNA expression profiles in 31 primary TNBC cases and in 13 lymph node metastases compared with 23 matched normal breast tissues to determine miRNAs associated with the initiation of this disease subtype and those associated with its metastasis. 71 miRNAs were differentially expressed in TNBC, the majority of which have previously been associated with breast cancer, including members of the miR-200 family and the miR-17-92 oncogenic cluster, suggesting that miRNAs involved in the initiation of TNBC are not subtype specific. However, the repertoire of miRNAs expressed in lymph node negative and lymph node positive TNBCs were largely distinct from one another. In particular, miRNA profiles associated with lymph node negative disease tended to be up-regulated, while those associated with lymph node positive disease were down-regulated and largely overlapped with the profiles of their matched lymph node metastases. miRNA expression profiles were examined in 31 primary TNBC cases and in 13 lymph node metastases compared with 23 matched normal breast tissues
2014-11-24 | E-GEOD-38167 | biostudies-arrayexpress
Project description:Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with no targeted therapeutics. The luminal androgen receptor (LAR), one of the six TNBC subtypes, constitutes 15% of TNBC and is enriched for AR and AR-target genes. Here, we show that a cohort of TNBC not only expresses full-length AR (AR-FL) at a much higher rate (~80%) than previously reported, but also expresses AR splice variants (AR-SVs) (~20%), subclassifying the LAR-TNBC subtype into LAR-FL, LAR-AR-SV, or dual positive. Higher AR and AR-SV expression and corresponding aggressive phenotypes were observed predominantly in specimens obtained from African American women. RNA sequencing of LAR TNBC specimens indicates an enrichment of hallmark interferon, JAK-STAT, and androgen signaling pathways, which were exclusive to AR-expressing epithelial cancer cells as demonstrated by spatial genomics. LAR and LAR-AR-SV TNBC cell proliferation, orthotopic cell line and patient-derived xenograft, and patient-derived tumor explants growth were inhibited by AR N-terminal domain (NTD)-binding selective AR degrader (SARD) that irreversibly inhibits AR or by the JAK inhibitor ruxolitinib. Subsequent biochemical analysis suggests that STAT1 is an AR coactivator, and SARD or ruxolitinib blocks this coactivation. Collectively, our work identifies and characterizes a pharmacologically targetable and previously unreported TNBC subtype predominantly in African American women and identifies a growth-promoting interaction between AR and JAK-STAT signaling.
2023-10-04 | GSE244272 | GEO
Project description:Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with no targeted therapeutics. The luminal androgen receptor (LAR), one of the six TNBC subtypes, constitutes 15% of TNBC and is enriched for AR and AR-target genes. Here, we show that a cohort of TNBC not only expresses full-length AR (AR-FL) at a much higher rate (~80%) than previously reported, but also expresses AR splice variants (AR-SVs) (~20%), subclassifying the LAR-TNBC subtype into LAR-FL, LAR-AR-SV, or dual positive. Higher AR and AR-SV expression and corresponding aggressive phenotypes were observed predominantly in specimens obtained from African American women. RNA sequencing of LAR TNBC specimens indicates an enrichment of hallmark interferon, JAK-STAT, and androgen signaling pathways, which were exclusive to AR-expressing epithelial cancer cells as demonstrated by spatial genomics. LAR and LAR-AR-SV TNBC cell proliferation, orthotopic cell line and patient-derived xenograft, and patient-derived tumor explants growth were inhibited by AR N-terminal domain (NTD)-binding selective AR degrader (SARD) that irreversibly inhibits AR or by the JAK inhibitor ruxolitinib. Subsequent biochemical analysis suggests that STAT1 is an AR coactivator, and SARD or ruxolitinib blocks this coactivation. Collectively, our work identifies and characterizes a pharmacologically targetable and previously unreported TNBC subtype predominantly in African American women and identifies a growth-promoting interaction between AR and JAK-STAT signaling.
2023-10-04 | GSE244282 | GEO
Project description:Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with no targeted therapeutics. The luminal androgen receptor (LAR), one of the six TNBC subtypes, constitutes 15% of TNBC and is enriched for AR and AR-target genes. Here, we show that a cohort of TNBC not only expresses full-length AR (AR-FL) at a much higher rate (~80%) than previously reported, but also expresses AR splice variants (AR-SVs) (~20%), subclassifying the LAR-TNBC subtype into LAR-FL, LAR-AR-SV, or dual positive. Higher AR and AR-SV expression and corresponding aggressive phenotypes were observed predominantly in specimens obtained from African American women. RNA sequencing of LAR TNBC specimens indicates an enrichment of hallmark interferon, JAK-STAT, and androgen signaling pathways, which were exclusive to AR-expressing epithelial cancer cells as demonstrated by spatial genomics. LAR and LAR-AR-SV TNBC cell proliferation, orthotopic cell line and patient-derived xenograft, and patient-derived tumor explants growth were inhibited by AR N-terminal domain (NTD)-binding selective AR degrader (SARD) that irreversibly inhibits AR or by the JAK inhibitor ruxolitinib. Subsequent biochemical analysis suggests that STAT1 is an AR coactivator, and SARD or ruxolitinib blocks this coactivation. Collectively, our work identifies and characterizes a pharmacologically targetable and previously unreported TNBC subtype predominantly in African American women and identifies a growth-promoting interaction between AR and JAK-STAT signaling.
2023-10-04 | GSE244271 | GEO
Project description:Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with no targeted therapeutics. The luminal androgen receptor (LAR), one of the six TNBC subtypes, constitutes 15% of TNBC and is enriched for AR and AR-target genes. Here, we show that a cohort of TNBC not only expresses full-length AR (AR-FL) at a much higher rate (~80%) than previously reported, but also expresses AR splice variants (AR-SVs) (~20%), subclassifying the LAR-TNBC subtype into LAR-FL, LAR-AR-SV, or dual positive. Higher AR and AR-SV expression and corresponding aggressive phenotypes were observed predominantly in specimens obtained from African American women. RNA sequencing of LAR TNBC specimens indicates an enrichment of hallmark interferon, JAK-STAT, and androgen signaling pathways, which were exclusive to AR-expressing epithelial cancer cells as demonstrated by spatial genomics. LAR and LAR-AR-SV TNBC cell proliferation, orthotopic cell line and patient-derived xenograft, and patient-derived tumor explants growth were inhibited by AR N-terminal domain (NTD)-binding selective AR degrader (SARD) that irreversibly inhibits AR or by the JAK inhibitor ruxolitinib. Subsequent biochemical analysis suggests that STAT1 is an AR coactivator, and SARD or ruxolitinib blocks this coactivation. Collectively, our work identifies and characterizes a pharmacologically targetable and previously unreported TNBC subtype predominantly in African American women and identifies a growth-promoting interaction between AR and JAK-STAT signaling.
2023-10-31 | GSE245202 | GEO
Project description:Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with no targeted therapeutics. The luminal androgen receptor (LAR), one of the six TNBC subtypes, constitutes 15% of TNBC and is enriched for AR and AR-target genes. Here, we show that a cohort of TNBC not only expresses full-length AR (AR-FL) at a much higher rate (~80%) than previously reported, but also expresses AR splice variants (AR-SVs) (~20%), subclassifying the LAR-TNBC subtype into LAR-FL, LAR-AR-SV, or dual positive. Higher AR and AR-SV expression and corresponding aggressive phenotypes were observed predominantly in specimens obtained from African American women. RNA sequencing of LAR TNBC specimens indicates an enrichment of hallmark interferon, JAK-STAT, and androgen signaling pathways, which were exclusive to AR-expressing epithelial cancer cells as demonstrated by spatial genomics. LAR and LAR-AR-SV TNBC cell proliferation, orthotopic cell line and patient-derived xenograft, and patient-derived tumor explants growth were inhibited by AR N-terminal domain (NTD)-binding selective AR degrader (SARD) that irreversibly inhibits AR or by the JAK inhibitor ruxolitinib. Subsequent biochemical analysis suggests that STAT1 is an AR coactivator, and SARD or ruxolitinib blocks this coactivation. Collectively, our work identifies and characterizes a pharmacologically targetable and previously unreported TNBC subtype predominantly in African American women and identifies a growth-promoting interaction between AR and JAK-STAT signaling.
2023-10-31 | GSE245554 | GEO
Project description:Recent meta-analyses suggest triple-negative breast cancer (TNBC) is a heterogenous disease. In this study we sought to define these TNBC subtypes and identify subtype-specific markers and targets. We identified and confirmed four distinct, stable TNBC subtypes: (1) Luminal-AR (LAR); 2) Mesenchymal (MES); 3) Basal-Like Immune-Suppressed (BLIS), and 4) Basal-Like Immune-Activated (BLIA). RNA profiling analysis was conducted on 198 TNBC tumors (ER-negativity defined as Allred Scale value â¤2) with >50% cellularity (discovery set: n=84; validation set: n=114)
2015-12-18 | E-GEOD-76124 | biostudies-arrayexpress
Project description:Breast cancer is the most common malignancy that develops in women, responsible for the highest cancer-associated death rates. Triple negative breast cancers (TNBC) represent an important subtype that have an aggressive clinical phenotype, are associated with a higher likelihood of metastasis and are not responsive to current targeted therapies. miRNAs have emerged as an attractive candidate for molecular biomarkers and treatment targets in breast cancer, but their role in the progression of TNBC remains largely unexplored. This study has investigated miRNA expression profiles in 31 primary TNBC cases and in 13 lymph node metastases compared with 23 matched normal breast tissues to determine miRNAs associated with the initiation of this disease subtype and those associated with its metastasis. 71 miRNAs were differentially expressed in TNBC, the majority of which have previously been associated with breast cancer, including members of the miR-200 family and the miR-17-92 oncogenic cluster, suggesting that miRNAs involved in the initiation of TNBC are not subtype specific. However, the repertoire of miRNAs expressed in lymph node negative and lymph node positive TNBCs were largely distinct from one another. In particular, miRNA profiles associated with lymph node negative disease tended to be up-regulated, while those associated with lymph node positive disease were down-regulated and largely overlapped with the profiles of their matched lymph node metastases.
2014-11-24 | GSE38167 | GEO
Project description:Recent meta-analyses suggest triple-negative breast cancer (TNBC) is a heterogenous disease. In this study we sought to define these TNBC subtypes and identify subtype-specific markers and targets. We identified and confirmed four distinct, stable TNBC subtypes: (1) Luminal-AR (LAR); 2) Mesenchymal (MES); 3) Basal-Like Immune-Suppressed (BLIS), and 4) Basal-Like Immune-Activated (BLIA).
2015-12-23 | GSE76274 | GEO
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype with few treatment options for chemo-resistant disease. In both preclinical models and patient circulating tumor cells, androgen receptor (AR) expression is increased in anchorage independent TNBC. The AR inhibitor enzalutamide (Enza) leads to reduced TNBC growth in soft agar, invasion, mammosphere formation in vitro, and reduced tumorigenicity and recurrence when combined with chemotherapy in vivo pre-clinical models. Transforming growth factor β (TGFβ) pathway gene signatures are also increased during TNBC anchorage independent survival both in vitro and in vivo in pre-clinical models and CTC from patients during relapse while on chemotherapy. We hypothesized that a positive loop between AR and TGFβ signaling facilitates TNBC anchorage independent survival (anoikis resistance). We previously published that AR protein levels and transcriptional activity increased during anchorage independent conditions and we now find that that multiple components of the TGFβ pathway, including TGFβ1 and 3, as well as pathway activity, as measured by nuclear localization and transcriptional activity of pSmad3, are enhanced in anchorage independent conditions. Indeed, exogenous TGFβ increased AR protein and TGFβ inhibition decreased AR and TNBC viability, particularly under anchorage independent culture conditions. ChIP-Seq experiments revealed AR binding to genomic regions near the TGFB1 and SMAD3. TGFB3 and AR expression were positively correlated in clinical datasets and high levels of co-expression correspond to significantly worse recurrence-free and overall survival in both ER- and basal-like breast cancer. Finally, combining Enza with a TGFβ inhibitor decreased cell survival more than either drug alone, particularly under anchorage independent conditions, where the effect was more than additive. These findings warrant further investigations into whether combined inhibition of AR and TGFβ pathways might decrease metastatic recurrence rates and mortality from TNBC.
2021-11-10 | GSE157862 | GEO