Luminal Androgen Receptor-Enriched tripple Negative Breast Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1087012 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Luminal Androgen Receptor-Enriched tripple Negative Breast Cancer
| PRJNA1087011 | ENA
Project description:Background: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employed an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. Results: The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer.
2024-01-30 | PXD047997 | Pride
Project description:Therapeutic strategies that improve survival outcomes for advanced-stage breast cancers have proven a major clinical challenge. Here, we define an androgen receptor signalling network that governs the maintenance and de novo formation of cancer stem cells in triple-negative breast cancer. In response to chemotherapy, androgen receptor activation switches cells into a cancer stem cell state, while androgen receptor antagonism suppresses cancer stem cell formation and function. In vivo, we validate that the androgen receptor antagonist, seviteronel, significantly improves chemotherapy-mediated inhibition of primary and metastatic tumour growth.
2023-12-03 | GSE184647 | GEO
Project description:Androgen receptor cell-autonomously regulates luminal cell plasticity [RNA-Seq]
| PRJNA1311814 | ENA
Project description:Androgen receptor cell-autonomously regulates luminal cell plasticity [ATAC-Seq]
| PRJNA1311816 | ENA
Project description:Many Luminal breast cancers are heterogeneous, containing substantial numbers of estrogen (ER-) and progesterone (PR-) receptor-negative cells among the ER+PR+ ones. Currently, the Basal-like ER-PR- Luminobasal subpopulation in Luminal disease is not targeted for treatment. To address the relationships between ER+PR+ and ER-PR- cells in Luminal cancers and tightly control their ratios, we have generated isogenic pure Luminal (pLUM) and pure Luminobasal (pLB) cells from the same parental Luminal human breast cancer cell line. We show that pLUM suppress proliferation of pLB cells in mixed-cell 3D colonies in vitro and in pLUM:pLB mixed-cell xenografts in mice. High-throughput screening of FDA-approved oncology drugs reveal pLB cells are sensitive to the EGFR inhibitors Gefitinib and Erlotinib. In mixed-cell 3D colonies and mixed-cell solid mouse tumors, combination therapy with the antiestrogen Fulvestrant and the EGFRi Gefitinib constitutes a robust treatment strategy. We propose that response to combination endocrine/EGFRi therapies in heterogeneous Luminal cancers will improve long-term survival in patients whose primary tumors have been preselected for the appropriate biomarkers.
2014-07-14 | GSE55350 | 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.
2023-10-04 | 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 | 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 | GSE244271 | GEO