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Unveiling alterations of epigenetic modifications and chromatin architecture leading to lipid metabolic reprogramming during the evolutionary trastuzumab adaptation of HER2-positive breast cancer [Cut & Tag]

ABSTRACT: Secondary trastuzumab resistance represents an evolutionary adaptation of HER2-positive breast cancer during anti-HER2 treatment. Most current studies have uncovered the alternations of HER2 and associated signaling pathways but pay less attention to broader cellular processes and their relevant genetic and epigenetic mechanisms. Here we have not only characterized transcriptome data but also examined epigenomic and 3D genome architecture information in both trastuzumab-sensitive and secondary-resistant breast cancer cells. Our findings reveal that the global metabolic reprogramming associated with trastuzumab resistance may stem from genome-wide alterations in both histone modifications and chromatin structure. Specifically, the transcriptional activities of key genes involved in lipid metabolism appear to be regulated by variant promoter H3K27me3 and H3K4me3 modifications, as well as promoter-enhancer interactions. These discoveries offer valuable insights into how cancer cells adapt to anti-tumor drugs and have the potential to impact future diagnostic and treatment strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244535 | GEO | 2023/10/08

REPOSITORIES: GEO

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Unveiling alterations of epigenetic modifications and chromatin architecture leading to lipid metabolic reprogramming during the evolutionary trastuzumab adaptation of HER2-positive breast cancer [RNA-Seq]

Project description:Secondary trastuzumab resistance represents an evolutionary adaptation of HER2-positive breast cancer during anti-HER2 treatment. Most current studies have uncovered the alternations of HER2 and associated signaling pathways but pay less attention to broader cellular processes and their relevant genetic and epigenetic mechanisms. Here we have not only characterized transcriptome data but also examined epigenomic and 3D genome architecture information in both trastuzumab-sensitive and secondary-resistant breast cancer cells. Our findings reveal that the global metabolic reprogramming associated with trastuzumab resistance may stem from genome-wide alterations in both histone modifications and chromatin structure. Specifically, the transcriptional activities of key genes involved in lipid metabolism appear to be regulated by variant promoter H3K27me3 and H3K4me3 modifications, as well as promoter-enhancer interactions. These discoveries offer valuable insights into how cancer cells adapt to anti-tumor drugs and have the potential to impact future diagnostic and treatment strategies.

2023-10-08 | GSE244533 | GEO

Unveiling alterations of epigenetic modifications and chromatin architecture leading to lipid metabolic reprogramming during the evolutionary trastuzumab adaptation of HER2-positive breast cancer

Project description:Secondary trastuzumab resistance represents an evolutionary adaptation of HER2-positive breast cancer during anti-HER2 treatment. Most current studies have tended to prioritize HER2 and its associated signaling pathways, often overlooking broader but seemingly less relevant cellular processes, along with their associated genetic and epigenetic mechanisms. Here, transcriptome data is not only characterized but also examined epigenomic and 3D genome architecture information in both trastuzumab-sensitive and secondary-resistant breast cancer cells. The findings reveal that the global metabolic reprogramming associated with trastuzumab resistance may stem from genome-wide alterations in both histone modifications and chromatin structure. Specifically, the transcriptional activities of key genes involved in lipid metabolism appear to be regulated by variant promoter H3K27me3 and H3K4me3 modifications, as well as promoter-enhancer interactions. These discoveries offer valuable insights into how cancer cells adapt to anti-tumor drugs and have the potential to impact future diagnostic and treatment strategies.

2023-10-08 | GSE244537 | GEO

Human HER2-breast cancer cell line, trastuzumab-resistant, LC-MSMS

Project description:We established an acquired trastuzumab-resistant model in vitro from a trastuzumab-sensitive, HER2-amplified breast-cancer cell line. A multi-omic strategy was implemented to obtain gene, proteome, and phosphoproteome signatures associated with acquired resistance to trastuzumab in HER2-positive breast cancer, followed by validation in human clinical samples.

2020-06-01 | PXD010574 | Pride

Treatment effects of trastuzumab and TDM-1 in a murine model of breast cancer brain metastasis

Project description:Background: Central nervous system (CNS) metastases represent a major problem in the treatment of HER2-positive breast cancer due to the disappointing efficacy of HER2-targeted therapies in the brain microenvironment. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in preclinical models of brain metastases. Methods: We treated mice bearing BT474 or MDA-MB-361 tumors in the CNS (N=9-11 per group), or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. All statistical tests were two-sided. Results: T-DM1 significantly delayed the growth of HER2-positive breast cancer brain metastases compared to trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a striking survival benefit (median survival for BT474 tumors: 28d for trastuzumab vs 112d for T-DM1, HR=6.2, 95% CI=6.1 to 85.84; P<.001). No difference in drug distribution and HER2-signaling was revealed between the two groups. However, T-DM1 led to a significant increase in tumor cell apoptosis (One-way ANOVA for ApopTag, p<.001), which was associated with mitotic catastrophe. Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven and PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted. Comparison of trastuzumab (n=4) and TDM-1 (n=4) treated BT-474 human breast carcinoma cells growing in murine brain

2015-11-09 | E-GEOD-69042 | biostudies-arrayexpress

Gene expression profiling of primary HER2-positive breast cancers treated with neoadjuvant trastuzumab

2016-03-31 | E-GEOD-62327 | biostudies-arrayexpress

Gene profiling of HER2 breast cancer patients treated with adjuvant trastuzumab

Project description:The human epidermal growth factor receptor 2 (HER2) gene encodes a tyrosine kinase receptor that controls important signal transduction pathways in breast cancer. Amplification and overexpression of the HER2 gene occurs in approximately 20% of breast cancers and is associated with an aggressive clinical phenotype. Trastuzumab, a humanized monoclonal antibody that targets HER2 showed exceptional efficacy in the treatment of breast cancer. In the adjuvant treatment of breast cancer patients, five randomized trials showed significant benefit of trastuzumab, with a reduction in the rate of recurrence of approximately 50% and improvement in the rate of survival of approximately 30%. In the current study, positive early stage breast cancer samples treated with adjuvant trastuzumab provided by institute Jules Bordet (IJB) and KUL. Gene expression and clinical outcome data were available. to better understand the genetic regulations and effects of the trastuzumab, we profile the the genes expression of positive early stage breast cancer samples treated with adjuvant trastuzumab.

2016-12-31 | GSE58984 | GEO

Gene expression profiling of primary HER2-positive breast cancers treated with adjuvant trastuzumab

Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients relapse after treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. To search for genes predictive of relapse in HER2-positive breast carcinoma patients treated with adjuvant trastuzumab, we conducted gene expression profiling analysis in 53 cases treated in the clinic with doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF) and trastuzumab. Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded tissues from 53 patients with primary HER2-positive (HER2+) tumors. The series consists in 23 relapsed and 30 non-relapsed cases with similar clinical-pathological characteristics (size, pathological lymph node involvement and estrogen receptor positivity) (3-year median follow up).

2015-10-19 | E-GEOD-55348 | biostudies-arrayexpress

A Phase II Randomized Trial of Neoadjuvant Trastuzumab or Lapatinib or the Combination of Trastuzumab and Lapatinib, Followed by Docetaxel and Carboplatin with Trastuzumab and/or Lapatinib in Patients with HER2+ Breast Cancer [treatments]

Project description:Adjuvant docetaxel, carboplatin, and trastuzumab (TCH) is a standard regimen for HER2+ breast cancer. Dual HER2-blockade with lapatinib (L) and trastuzumab demonstrated significant activity in the metastatic and neoadjuvant settings. This study evaluates neoadjuvant TC plus trastuzumab (H) and/or lapatinib (L). This study demonstrated a similar pCR rate with TCH and TCHL and a lower rate of pCR with TCL. Treatment-related toxicity limited the ability for participants to receive protocol-specified chemotherapy and HER2-targeted therapy in the TCHL Arm.

2019-05-08 | GSE130787 | GEO

2019-05-08 | GSE130786 | GEO

Trastuzumab produces therapeutic actions by upregulating miR-26a and miR-30b in breast cancer cells

Project description:Objective: Trastuzumab has been used for the treatment of HER2-positive breast cancer (BC). However, a subset of BC patients exhibited resistance to trastuzumab therapy. Thus, clarifying the molecular mechanism of trastuzumab treatment will be beneficial to improve the treatment of HER2-positive BC patients. In this study, we identified trastuzumab-responsive microRNAs that are involved in the therapeutic effects of trastuzumab. Methods and results: RNA samples were obtained from HER2-positive (SKBR3 and BT474) and HER2-negetive (MCF7 and MDA-MB-231) cells with and without trastuzumab treatment for 6 days. Next, we conducted a microRNA profiling analysis using these samples to screen those microRNAs that were up- or downregulated only in HER2-positive cells. This analysis identified miR-26a and miR-30b as trastuzumab-inducible microRNAs. Transfecting miR-26a and miR-30b induced cell growth suppression in the BC cells by 40% and 32%, respectively. A cell cycle analysis showed that these microRNAs induced G1 arrest in HER2-positive BC cells as trastuzumab did. An Annexin-V assay revealed that miR-26a but not miR-30b induced apoptosis in HER2-positive BC cells. Using the prediction algorithms for microRNA targets, we identified cyclin E2 (CCNE2) as a target gene of miR-30b. A luciferase-based reporter assay demonstrated that miR-30b post-transcriptionally reduced 27% (p=0.005) of the gene expression by interacting with two binding sites in the 3’-UTR of CCNE2. Conclusion: In BC cells, trastuzumab modulated the expression of a subset of microRNAs, including miR-26a and miR-30b. The upregulation of miR-30b by trastuzumab may play a biological role in trastuzumab-induced cell growth inhibition by targeting CCNE2. We obtained microRNA expression profiles of breast cancer cell lines, MCF7, MDA-MB-231, SKBR3, and BT474, with or without trastuzumab (4microgram/mL) treatment.

2012-06-02 | E-GEOD-38415 | biostudies-arrayexpress

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