HR+/HER2- Breast Cancer Cell and Normal Breast Epithelial Cell Derived Exosome RNA Expression
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ABSTRACT:
PROVIDER: PRJNA854659 | ENA |
REPOSITORIES: ENA
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Project description:AS a key medium for intercellular communication, exosome plays an important role in the occurrence and development of various forms of cancers, including breast cancer. However, the RNA from breast cancer-derived exosome remains to be explored. The HR+/HER2− breast cancer is the most common subgroup of breast cancer, we collected and primary cultured breast cancer and normal breast epithelial cells from three HR+/HER2− breast cancer patients, isolated the supernatant and extracted RNA from exosomes, and then performed microarray assays.
2023-10-01 | GSE207304 | GEO
Project description:Hormone receptor (HR)-positive, HER2-positive breast cancers are resistant to endocrine and anti-HER2 therapies due to crosstalk between estrogen receptor (ER) and HER2. However, how anti-HER2 agents activate ER as a mechanism of resistance remains unknown. Using single-cell RNA sequencing, we identified Bromodomain Containing Protein 8 (BRD8) as a major mediator of ER activation in response to neratinib, a HER2 tyrosine kinase inhibitor. BRD8 expression was rapidly induced by various anti-HER2 agents (neratinib, lapatinib and trastuzumab) and its expression positively correlates with ER. BRD8 regulates both ER-dependent and -independent growth promoting pathways. Moreover, BRD8 ablation re-sensitizes fulvestrant- or neratinib-resistant HR+/HER2+ cells to neratinib, suggesting that combinatorial targeting of BRD8 and HER2 attenuates signal crosstalk and possibly overcomes treatment resistance to dual anti-ER/HER2 blockade therapy. This work identifies BRD8 as not only a central hub for ER signaling activation upon anti-HER2 treatment, but also a druggable vulnerability for treating HR+/HER2+ breast cancer.
2026-03-20 | GSE230327 | GEO
Project description:Hormone receptor (HR)-positive, HER2-positive breast cancers are resistant to endocrine and anti-HER2 therapies due to crosstalk between estrogen receptor (ER) and HER2. However, how anti-HER2 agents activate ER as a mechanism of resistance remains unknown. Using single-cell RNA sequencing, we identified Bromodomain Containing Protein 8 (BRD8) as a major mediator of ER activation in response to neratinib, a HER2 tyrosine kinase inhibitor. BRD8 expression was rapidly induced by various anti-HER2 agents (neratinib, lapatinib and trastuzumab) and its expression positively correlates with ER. BRD8 regulates both ER-dependent and -independent growth promoting pathways. Moreover, BRD8 ablation re-sensitizes fulvestrant- or neratinib-resistant HR+/HER2+ cells to neratinib, suggesting that combinatorial targeting of BRD8 and HER2 attenuates signal crosstalk and possibly overcomes treatment resistance to dual anti-ER/HER2 blockade therapy. This work identifies BRD8 as not only a central hub for ER signaling activation upon anti-HER2 treatment, but also a druggable vulnerability for treating HR+/HER2+ breast cancer.
2026-03-20 | GSE230326 | GEO
Project description:Hormone receptor (HR)-positive, HER2-positive breast cancers often develop resistance to endocrine and anti-HER2 therapies due to the heterogeneous expression of estrogen receptor (ER) and HER2 and the crosstalk of these growth-promoting pathways. However, how anti-HER2 agents activate ER and other growth-promoting pathways remains unknown. Single-cell RNA sequencing of BT474 breast cancer cells identified Bromodomain Containing Protein 8 (BRD8), an acetyl-lysine reader protein in the histone acetylase EP400 complex, as a pivotal mediator to activate ER in response to neratinib treatment. BRD8 expression was rapidly induced by various anti-HER2 agents (neratinib, lapatinib, and trastuzumab), and its depletion disrupted the crosstalk between ER and HER2 signaling pathways and rendered HR+/HER2+ cells and tumor organoids more sensitive to anti-HER2 agents. BRD8, ER, and ER target genes are co-induced by neratinib in single-nucleus (sn) RNA sequencing of a patient-derived xenograft (PDX). Concomitantly, SnATAC-seq reveals that the activated genes share open chromatin regions enriched in transcription factors (TF) binding motifs of ER, forkhead box (FOX), and ETS family. Since EP400 enhances H2AZ deposition and acetylation on chromatin, we performed H2AZ and H2AZac ChIP-sequencing in the presence or absence of BRD8 and neratinib treatment. Upon neratinib treatment, BRD8 activates ER, FOX, and ETS target genes through modulating H2AZac deposition and chromatin decompaction. This finding coincides with RNA-sequencing, where BRD8 promotes cell growth in an ER-dependent and independent manner. In line with these findings, patients who responded poorly to the anti-HER2 therapies exhibited higher BRD8 gene signatures. Furthermore, BRD8 knockdown ablates the ER and HER2 signaling crosstalk and re-sensitizes neratinib-resistant HR+/HER2+ cells to neratinib. Together, this work not only explains why ER signaling is activated upon anti-HER2 therapies but also identifies BRD8 as a druggable vulnerability in HR+/HER2+ breast cancer.
2026-03-19 | GSE286038 | GEO
Project description:Hormone receptor (HR)-positive, HER2-positive breast cancers often develop resistance to endocrine and anti-HER2 therapies due to the heterogeneous expression of estrogen receptor (ER) and HER2 and the crosstalk of these growth-promoting pathways. However, how anti-HER2 agents activate ER and other growth-promoting pathways remains unknown. Single-cell RNA sequencing of BT474 breast cancer cells identified Bromodomain Containing Protein 8 (BRD8), an acetyl-lysine reader protein in the histone acetylase EP400 complex, as a pivotal mediator to activate ER in response to neratinib treatment. Since EP400 enhances H2AZ deposition and acetylation on chromatin, we performed H2AZ and H2AZac ChIP-sequencing in the presence or absence of BRD8 and neratinib treatment. This will help us address how BRD8 regulates ER as well as other growth factors.
2026-03-19 | GSE283036 | GEO
Project description:HR+HER2- breast cancers resistant to palbociclib-hormone therapy displayed increased lipid uptake and expression of stress response proteins (GPX4, PSMA7), by adding ferroptosis inducers to palbocilib-fulvestrant combination therapy, tumor response was enhanced in three different pre-clinical models: resistant cells, xenografts and PDX.
2025-01-06 | GSE270021 | GEO
Project description:Stage-related transcriptional changes in HR-positive/HER2-negative breast cancer
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Project description:Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the most common type of breast cancer, is facing challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2- breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of HR+/HER2- breast cancer patients (n = 351) and revealed that HR+/HER2- breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2- breast cancer was related to MAP3K1 mutation and we validated experimentally that MAP3K1 mutation could attenuate CD8+ T cell-mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I-mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNAs, thereby driving tumor immune escape. In preclinical models, the postbiotics tyramine could reverse the MAP3K1 mutation-induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy.
2024-12-20 | GSE276527 | GEO
Project description:Breast cancer, categorised into hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative (TNBC) subtypes, exhibits varied outcomes based on the number of tumour-infiltrating lymphocytes (TILs). Increased TIL levels are associated with better outcomes in HER2+ and TNBC, while HR+ individuals with high TIL levels show shorter survival but greater neoadjuvant chemotherapy response. To explore the divergent roles of TIL levels across various subtypes and their effect on immune cell composition, we employed single-cell RNA sequencing on 31 patients with breast cancer. HR+ breast cancer with high TIL levels (TIL-high) revealed increased SPP1+ macrophages, increased SPP1 expression in other monocytes/macrophages (mono/macro) subgroups, and enriched pathways associated with extracellular matrix (ECM) remodelling in mono/macro. Moreover, cell–cell interaction analyses revealed enhanced SPP1, MIF, and FN1 signalling in the interaction between SPP1+ macrophages and T-cells in TIL-high HR+ breast cancer. Spatial transcriptomics data highlighted the close proximity of SPP1+ macrophages, CD8+ T-cells, and CD4+ T-cells in TIL-high HR+ breast cancer. Our findings unveil the novel influence of SPP1+ macrophages on T-cells in TIL-high HR+ breast cancer, potentially explaining the poor prognosis and offering insights for targeted interventions.
2024-10-09 | GSE261774 | GEO
Project description:Intrinsic and acquired resistance to CDK4/6 inhibitors (CDK4/6i) is a critical challenge in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). CDK2 inhibitors (CDK2i) show promise in this context, with several currently under early-phase clinical evaluation. Here, by analyzing tumor and liquid biopsies from patients treated with the selective CDK2i PF-07104091, we observed that PF-07104091 monotherapy achieved disease stabilization in a cohort of CDK4/6i-resistant HR+/HER2- MBC patients. Notably, responses were observed irrespective of RB expression and phosphorylation, whereas non-progressive disease appeared more frequently among patients whose tumors retained wild-type TP53. Studies in established and patient-derived cell lines further substantiated that the growth suppressive effects of CDK2i were independent of RB status in CDK4/6i-resistant models. CDK2i activity reduced DNA replication rate, increased DNA damage, and inhibited mitotic entry, with growth inhibition dependent on p53 expression. These findings indicate that CDK dependency shifts from CDK4/6 toward CDK2 as cells transition from CDK4/6i-sensitive to CDK4/6i-resistant state. The distinct mechanisms of CDK2i and CDK4/6i support enhanced synergistic activity in HR+/HER2- MBC with acquired resistance to CDK4/6i therapy.
2026-05-14 | GSE265952 | GEO