Microarray gene expression profiles from female ER-positive HER2-normal breast cancer patients
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PROVIDER: PRJNA967036 | ENA |
REPOSITORIES: ENA
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Project description:Diagnostic samples from female breast cancer patients with ER-positive and HER2-normal tumors selected for neoadjuvant chemotehrapy.
2023-05-09 | GSE231629 | 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:Hormones and growth factors accelerate cell proliferation of breast cancer cells, and these molecules are well investigated targets for drug development and application. The mechanisms of cell proliferation of breast cancers lacking estrogen receptor (ER) and HER2 have not been fully understood. The purpose of the present study is to find genes that are differentially expressed in breast cancers and that might significantly contribute to cell proliferation in these cancers. Forty tumor samples, consisting of ten each of immunohistochemically ER(+)/HER2(-), ER(+)/HER2(+), ER(-)/HER2(+), and ER(-)/HER2(-) cancer were analyzed using oligonucleotide microarrays. Both genes and tumor samples were subjected to hierarchical clustering. ER(+)/HER2(-) breast cancers and ER(-)/HER2(-) cancers tended to form a tumor cluster, but HER2 positive breast cancers were split into different tumor clusters. Significant differential expression between IHC-ER(-)/HER2(-) and other tumors was defined as having an expression level at least 2-fold higher or 2-fold lower, and analyzed by multi-step two-way ANOVA. Genes overexpressed differently in IHC-ER(-)/HER2(-) breast cancers compared to other all three types were 8 genes (FABP7, GABRP, GAL, CXCL13, CDC42EP4, C2F, FOXM1, CSDA), and underexpressed genes were nine including ITGB5, KIAA0310, MAGED2, PRSS11, SORL1, TGFB3, KRT18, CPE, BCAS1. No gene was directly related to cell proliferation such as cyclins, cyclin-dependent kinase, p53, p16, and the pRb and p21 families. We had a particular focus on a transcriptional factor E2F-5 from a list of genes overexpressed in ER negative breast cancers compared to ER positive breast cancers, and further examined. Gene amplification of E2F-5 was detected in 5/57 (8.8%) in breast cancers by FISH. No point mutation was found at the binding domain with DNA or dimerization partner of E2F-5. Immunohistochemically E2F-5 positive cancers were more frequent in ER(-)/HER2(-) cancer (14/27, 51.9%) than in other types of cancer (5/30, 16.7%) (p=0.05). E2F-5 positive cancers had higher Ki-67 labeling index (59.5%) than E2F-5 negative cancers (36.3%). E2F-5 positive cancers showed higher histological grade including metaplastic carcinoma, and worse clinical outcome with shorter disease free survival in node negative patients. In conclusion, we demonstrated that there is a population of breast cancer with overexpression of a cell cycle related transcriptional factor E2F-5. E2F-5 positive breast cancers were frequent in ER(-)/HER2(-) group with high Ki-67 labeling index, high histological grade and worse clinical outcome. Keywords: immunohistochemical phenotype
2009-03-14 | GSE6367 | GEO
Project description:This study is intended to investigate the differences in biological molecular expression upon HER2 status (HER2-positive and –negative) in AR-positive, ER-/PR-negative breast cancer. Results indicate that differentially expressed genes were involved in olfactory transduction, major histocompatibility complex, ECM-receptor interaction, focal adhesion, adherens junction, as well as protein processing in endoplasmic reticulum.
2019-06-30 | GSE92252 | 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:The goal of our study is to build an integrated transcriptome landscape model for HER2 positive breast tumors and identify the crucial signaling pathways associated with HER2 tumors. Genomic features include, 685 genes that were differentially expressed only in HER2-positive tumors, 102 genes that were alternatively spliced in a pattern that is unique to HER2-positive tumors, and 303 genes that expressed single nucleotide sequence variants (eSNVs) that were unique to HER2-positive tumors. Network analysis was performed to integrate the genomic features into a transcriptome landscape model that identified 12 highly interconnected cellular processes that appear to be critical to the establishment and maintenance of HER2-positive tumors. We observed that integrin signaling was linked to lapatinib sensitivity in vitro and strongly associated with risk of relapse in the NCCTG N9831 adjuvant trastuzumab clinical trial dataset. We analyzed RNA-seq data from a survey panel consisting of 8 benign breast lesions, 8 ER+, 8 triple negative, and 8 HER2-positive primary breast tumors to identify genomic features that were uniquely associated with HER2-positive tumors
2013-12-06 | E-GEOD-45419 | biostudies-arrayexpress
Project description:Estrogen receptor positive (ER+) breast cancers that develop resistance to therapies that target the ER are the most common cause of breast cancer death. Beyond mutations in ER, which occur in 25-30% of patients treated with aromatase inhibitors (AIs), our understanding of clinical mechanisms of resistance to ER-directed therapies remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to ER-directed agents, including AIs, tamoxifen, and fulvestrant. Examination of treatment-naïve primary tumors in five patients revealed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. These mutations were mutually exclusive with ER mutations, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that these mutations conferred estrogen independence. In addition, and in contrast to ER mutations, these mutations resulted in resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib, highlighting an effective treatment strategy in these patients.
2018-10-19 | GSE121411 | GEO
Project description:The use of trastuzumab and pertuzumab in combination with docetaxel for initial treatment of HER2-positive breast cancer patients has resulted in notable clinical benefits in comparison to docetaxel administered with trastuzumab alone. Nevertheless, although therapeutic success is evident at the outset, the majority of tumours eventually advance, rendering metastatic disease and subsequent recurrence in patients who have developed acquired resistance. There is an urgent requirement to enhance our comprehension of the mechanisms governing resistance, enabling us to develop targeted therapeutic approaches to improve efficacy. We produced four HER2-positive-derived cell lines through prolonged exposure to trastuzumab and pertuzumab, determining their resistance rates. We confirmed long-term resistance through a notable increase in colony formation capacity of the derived cells. We confirmed the molecular identity of the new cell lines using immunohistochemistry of their receptors and profiling of point mutations. We detected HER2 overexpression in all cell lines and resistance to trastuzumab and pertuzumab did not result in variations in ER, PR and HER2 receptor expression. Finally, a study using proteomics analysis confirmed a significant alteration in the abundance patterns of over 600 proteins. This has implications for various vital biological processes such as ribosome creation, mitochondrial functionality, and metabolism. These mechanisms may play a crucial role in developing resistance in HER2-positive breast cancer. We conclude that these BCCLs resistant to trastuzumab plus pertuzumab-based anti-HER2 therapy could be a useful resource to enhance comprehension of resistance acquisition mechanisms.
2024-01-26 | PXD045804 | Pride