NGS data of ER+/HER2- breast carcinoma patients
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PROVIDER: PRJEB58369 | ENA |
REPOSITORIES: ENA
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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: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: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:Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies
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Project description:Microarray gene expression profiles from female ER-positive HER2-normal breast cancer patients
| PRJNA967036 | ENA
Project description:Background MicroRNA expression is frequently dysregulated in cancer and it could be used potentially as a disease classifier and a prognostic tool in cancer. It has been reported that the cancer associated specific microRNAs were stably detected in blood. The objective of this study was to discover a panel of circulating microRNAs as potential ER+/HER2- breast cancer biomarkers. Methods We compared levels of circulating microRNAs in blood samples from 11 ER+/HER2- advanced breast cancer patients with age-matched 5 control subjects by using microarray-based expression profiling. We validated the level of microRNAs by real-time quantitative polymerase cycle reaction (RT-qPCR) in 40 control subjects, 180 early breast cancer patients (EBC), and 52 metastatic breast cancer patients (MBC). Then, we assessed the association between the levels of microRNA and clinical outcomes of ER+/HER2- metastatic breast cancer. Background MicroRNA expression is frequently dysregulated in cancer and it could be used potentially as a disease classifier and a prognostic tool in cancer. It has been reported that the cancer associated specific microRNAs were stably detected in blood. The objective of this study was to discover a panel of circulating microRNAs as potential ER+/HER2- breast cancer biomarkers. Methods We compared levels of circulating microRNAs in blood samples from 11 ER+/HER2- advanced breast cancer patients with age-matched 5 control subjects by using microarray-based expression profiling. We validated the level of microRNAs by real-time quantitative polymerase cycle reaction (RT-qPCR) in 40 control subjects, 180 early breast cancer patients (EBC), and 52 metastatic breast cancer patients (MBC). Then, we assessed the association between the levels of microRNA and clinical outcomes of ER+/HER2- metastatic breast cancer. Controls: 5 cases; ER +/HER2- breast cancer patients : 11 cases
2013-12-12 | E-GEOD-53179 | biostudies-arrayexpress
Project description:Background MicroRNA expression is frequently dysregulated in cancer and it could be used potentially as a disease classifier and a prognostic tool in cancer. It has been reported that the cancer associated specific microRNAs were stably detected in blood. The objective of this study was to discover a panel of circulating microRNAs as potential ER+/HER2- breast cancer biomarkers. Methods We compared levels of circulating microRNAs in blood samples from 11 ER+/HER2- advanced breast cancer patients with age-matched 5 control subjects by using microarray-based expression profiling. We validated the level of microRNAs by real-time quantitative polymerase cycle reaction (RT-qPCR) in 40 control subjects, 180 early breast cancer patients (EBC), and 52 metastatic breast cancer patients (MBC). Then, we assessed the association between the levels of microRNA and clinical outcomes of ER+/HER2- metastatic breast cancer. Background MicroRNA expression is frequently dysregulated in cancer and it could be used potentially as a disease classifier and a prognostic tool in cancer. It has been reported that the cancer associated specific microRNAs were stably detected in blood. The objective of this study was to discover a panel of circulating microRNAs as potential ER+/HER2- breast cancer biomarkers. Methods We compared levels of circulating microRNAs in blood samples from 11 ER+/HER2- advanced breast cancer patients with age-matched 5 control subjects by using microarray-based expression profiling. We validated the level of microRNAs by real-time quantitative polymerase cycle reaction (RT-qPCR) in 40 control subjects, 180 early breast cancer patients (EBC), and 52 metastatic breast cancer patients (MBC). Then, we assessed the association between the levels of microRNA and clinical outcomes of ER+/HER2- metastatic breast cancer.
2013-12-12 | GSE53179 | GEO
Project description:We identified a 17-gene Her2-enriched tumor initiating cell (HTIC) signature in MMTV-Her2/Neu mouse mammary TICs. Here, we show that patients with HTICS+ HER2+:ERα− tumors are more likely to achieve a pathologic complete response to trastuzumab-based neoadjuvant chemotherapy compared with HER2+:ER+ tumors.
2012-05-12 | GSE37946 | GEO
Project description:Circulating tumour cells in women with advanced oestrogen-receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER+/HER2- primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2+ and HER2- subpopulations: HER2+ circulating tumour cells are more proliferative but not addicted to HER2, consistent with activation of multiple signalling pathways; HER2- circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2- circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2+ and HER2- circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2- phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance. Seventy-four single candidate CTCs from two representative ER+/HER2- patients (BRx-42 and BRx-82) and 14 triple negative patients were isolated via micromanipulation and subjected to single-cell RNA-sequencing. Thirteen candidate CTCs expressed PTPRC at a level higher than 10 reads-per-million, so were deemed potential White Blood Cells and therefore dropped from further consideration. Expression profiles of CTCs expressing ERBB2 at a level greater than 10 RPM were compared with those expressing ERBB2 at a level less than 10 RPM.
2016-08-25 | E-GEOD-75367 | biostudies-arrayexpress
Project description:Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial (ClinicalTrials.gov Identifier: NCT01875666, LCCC1214) designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 transcription factor expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. Patient samples from this trial, when sufficient material was available, were also subjected to kinase enrichment using multiplexed kinase inhibitor bead affinity chromatography and LC-MS/MS. Strongly responsive transcriptional responses observed in a subset of patients corresponded to decreased binding of CDK1 and DDR1 by our proteomic approach. Taken together, our results highlight the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.
2021-04-09 | PXD021865 | Pride