CircPVT1 promotes ER-positive breast tumorigenesis and drug resistance by targeting ESR1 and MAVS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA911306 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22692677_1.fastq.gz | Fastqsanger.gz | |||
| SRR22692677_2.fastq.gz | Fastqsanger.gz | |||
| SRR22692678_1.fastq.gz | Fastqsanger.gz | |||
| SRR22692678_2.fastq.gz | Fastqsanger.gz | |||
| SRR22692679_1.fastq.gz | Fastqsanger.gz |
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Project description:The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and endocrine therapy resistance remain incompletely understood. Here, we reported that circPVT1, a circular RNA generated from lncRNA PVT1, is highly expressed in ERalpha-positive breast cancer cell lines and tumor samples, which is functionally important in promoting ERalpha-positive breast tumorigenesis and endocrine therapy resistance. CircPVT1 acts as a competing endogenous RNA (ceRNA) to sponge miR-181a-2-3p, promoting the expression of ESR1 and downstream ERalpha-target genes and breast cancer cell growth. Meanwhile, circPVT1 directly interacts with MAVS to disrupt the RIGI-MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway and anti-tumor immunity. The dual mechanisms both contribute to ERα-positive breast tumorigenesis. Anti-sense oligonucleotides (ASO) targeting circPVT1 was shown to inhibit ERalpha-positive breast cancer cell and tumor growth, and could re-sensitize tamoxifen-resistant ERalpha-positive breast cancer cells to tamoxifen treatment. Taken together, our data demonstrated that circPVT1 can work through both ceRNA and protein scaffold mechanisms to promote cancer, and in particular, circPVT1 may serve as a diagnosis biomarker and therapeutic target for ERalpha-positive breast cancer in the clinic.
2023-02-06 | GSE220776 | GEO
Project description:The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and endocrine therapy resistance remain incompletely understood. Here, we report that circPVT1, a circular RNA generated from the lncRNA PVT1, is highly expressed in ERα-positive breast cancer cell lines and tumor samples and is functionally important in promoting ERα -positive breast tumorigenesis and endocrine therapy resistance. CircPVT1 acts as a competing endogenous RNA (ceRNA) to sponge miR-181a-2-3p, promoting the expression of ESR1 and downstream ERα-target genes and breast cancer cell growth. Further, circPVT1 directly interacts with MAVS protein to disrupt the RIGI-MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway and anti-tumor immunity. Anti-sense oligonucleotides (ASO) targeting circPVT1 inhibits ERα-positive breast cancer cell and tumor growth, re-sensitizing tamoxifen-resistant ERα-positive breast cancer cells to tamoxifen treatment. Taken together, our data demonstrated that circPVT1 can work through both ceRNA and protein scaffolding mechanisms to promote cancer. Thus, circPVT1 may serve as a diagnostic biomarker and therapeutic target for ERα-positive breast cancer in the clinic.
| S-SCDT-10_15252-EMBJ_2022112408 | biostudies-other
Project description:Estrogen receptor α (ER) positivity defines ~75% of breast cancers (BCs), treated with a variety of estrogen-targeting therapies. However, ~25% of patients with localized disease and nearly all metastatic disease patients develop resistance to such therapies. One major mechanism of resistance occurs through gain-of-function mutations in the gene encoding ER (ESR1), which occurs after prolonged endocrine therapy. These gain-of-function mutations render ESR1 constitutively active and represent critical neoepitopes of ER+ BC. We here confirm that these mutations permit ligand-independent estrogen signaling, as well as stimulate alternate pathways to enhance BC oncogenicity in vivo. As these oncogenic ESR1-mutated genes (ESR1mut) may be a significant, predictable contributor to the development of acquired resistance to endocrine therapy, we explored the potential of vaccination targeting these neoepitopes. In our study, we confirmed that these peptides are presented by MHC complexes and capable of stimulating CD8+ T-cell responses. Using recombinant adenoviral vectors encoding ESR1mut, we also demonstrate the induction of ESR1-specific immunity to generate anti-tumor responses against ESR1mut-expressing BC. Finally, we improved the safety profile, ESR1-specific immunity and anti-tumor efficacy of our vaccines using c-terminal subunit ESR1mut targeting, which has the potential to prevent the outgrowth of resistant ER+ BCs and improve patient outcomes.
2024-02-14 | GSE153033 | GEO
Project description:Three quarters of all breast cancer cases express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancers, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and outwith direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry (MS) based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and MTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells.
2024-03-26 | PXD032404 | Pride
Project description:Three quarters of all breast cancer cases express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancers, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and outwith direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry (MS) based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and MTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells.
2024-03-26 | PXD032369 | Pride
Project description:To understand the interactions between ER-alpha and PR interactions with chromatin in Esr1-wildtype versus mutant mammary cells, ChIP-seq was performed against both transcription factors. Animals were treated for four days with E2 and P4, then harvested for analysis.
2023-05-07 | GSE186452 | GEO
Project description:Three quarters of all breast cancer cases express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancers, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and outwith direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry (MS) based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and MTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells.
2024-03-26 | PXD032285 | Pride
Project description:Three quarters of all breast cancer cases express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancers, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and outwith direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry (MS) based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and MTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells.
2024-03-26 | PXD046446 | Pride
Project description:Purpose: Breast cancers with ESR1 mutations are resistant to antiestrogen therapy. We aimed to investigate the association of ESR1 mutations with resistance to CDK4/6 inhibitors (CDK4/6i) using real-world data analysis and experimental validation. Patients and Methods: A total of 3,958 patients with estrogen receptor-positive (ER+) metastatic breast cancer with DNA sequencing data were analyzed. Breast tumor DNA and circulating tumor (ct) DNA were sequenced using the Tempus xT tumor assay and Tempus xF liquid biopsy, respectively. Patients were stratified into either treated with CDK4/6i (breast tumors: 1,070; ctDNA: 1,885) or CDK4/6i naïve (breast tumors: 750; ctDNA: 253). Engineered MCF7 cells carrying ESR1 Y537S or D538G knock-in mutations were used to study antitumor efficacy of the CDK4/6i, palbociclib in vitro and in vivo. Results: In both xF and xT assays, ESR1 mutations were the only somatic alterations significantly more frequent in those who received CDK4/6i than those who did not. Knock-in of ESR1 Y537S or ESR1 D538G in MCF7 cells resulted in upregulation of cell cycle-related gene signatures upon treatment with CDK4/6i ± antiestrogen compared to cells with non-mutant ESR1. MCF7 xenografts harboring ESR1 Y537S and D538G mutations established in nude mice were resistant to palbociclib. Conclusions: We report herein real-world and preclinical evidence that ESR1 mutations, particularly Y537S and D538G, can drive resistance to CDK4/6 inhibitors.
2024-11-12 | GSE281302 | GEO
Project description:We investigated the therapeutic potential of BET inhibition to target ESR1 mutation-induced “transcriptional addiction” in ER-positive breast cancer. Our studies show that ESR1 mutant (Y537S and D538G) cells activate unique transcriptional programs that are targeted by OTX015, a BET inhibitor
2022-06-18 | GSE206185 | GEO