RNA-Seq of human breast cancer cells MCF7 treated with EPZ004777 or DMSO for 3 or 6 days
Ontology highlight
ABSTRACT:
INSTRUMENT(S): NextSeq 500
ORGANISM(S): Homo sapiens
SUBMITTER: Alessandro Weisz
PROVIDER: E-MTAB-6875 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:NascentSeq performed of human breast cancer MCF7 cell lines after treatment with EPZ, ICI and DMSO after 3 days and 6 days
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Project description:Breast Cancer (BC) is one of the main causes of cancer-related death in women. The most widespread BC subtype (75%) is the hormone-dependent, characterized by high expression of Estrogen Receptor Alpha (ERa). ERa exerts its oncogenic activity through the interaction with different co-regulators, carrying out a direct control on gene transcription and thus being the target of specific anticancer therapies. Despite the efficiency of these drugs, 30% of patients develop de novo or acquired resistance mechanisms, caused by alternative mechanisms that bypass antiestrogenic effects determining the onset of relapse. In order to identify new and potentially drugable Era molecular partners, essential genes for BC progression in luminal cell lines assessed by CRISPR-cas assay were compared to ERa interactome, dropping our focus on the tyrosine-protein kinase BAZ1B. BAZ1B is an essential component of the WICH complex and plays a crucial role in chromatin remodelling acting also as transcription regulator. In order to characterize the functional role of BAZ1B in luminal BC, we first employed a TCGA analysis that showed higher expression of BAZ1B in luminal BC associated with a worst overall survival and progression free survival of patient affected by this disease. A transcriptome profiling after BAZ1B silencing was performed in MCF-7 cells, highlighting an impact of modulated genes in key BC pathways including the estrogen signalling. BAZ1B silencing showed also an effect on cell growth, inhibiting cell proliferation and increasing apoptosis activation mechanisms promoted by the loss of ERa protein expression coupled to a reduction of the receptor transactivation activity. Interesting, these effects were confirmed also in antiestrogen (Tamoxifen and Fulvestrant) resistant BC cell models that retain ERa expression, suggesting BAZ1B as a novel and potentially exploitable therapeutic target in the treatment of both hormone dependent and resistant mammary tumours.
2022-07-25 | E-MTAB-11142 | biostudies-arrayexpress
Project description:ChIP-Seq of ERalpha and DOT1L in MCF7 cell before and after EPZ and ICI treatment
2019-02-08 | E-MTAB-6883 | biostudies-arrayexpress
Project description:Estrogen Receptor αlpha (ERα) is the master regulator of estrogen signaling in hormone-responsive breast cancer (BC), however epigenetic mechanisms, including DNA methylation, are emerging as key processes for regulation of critical cell functions including tumorigenesis. We have recently reported the epigenetic writer DOT1L (DOT1 Like Histone Lysine Methyltransferase) to associated to ERα, part of chromatin bound multiprotein complex and that the pharmacological inhibition of this enzyme reduces the transcription rate of several genes involved in ERα-mediated signaling leading to inhibition of BC cell proliferation. Here, we investigated the functional impact of DOT1L inhibition on methylome changes in BC and its possible contribution to deregulation of transcriptional pathways associated to the progression of this disease.
2023-02-21 | E-MTAB-12635 | biostudies-arrayexpress
Project description:Estrogen Receptor alpha (ERα), a nuclear receptor with transcriptional activity, is a master regulator of estrogen signaling, widely known as therapeutic target in hormone-responsive breast cancer (BC). Moreover, ERα is highly expressed in approximately 80% of High Grade Serous Ovarian Cancer (HGSOC), the most common epithelial ovarian carcinoma. Despite some promising clinical trials evaluating endocrine therapy in this type of tumor, the role of ERα is still unknown. Epigenetic changes, such as DNA methylation, are emerging as key contributing factors to carcinogenesis. Disruptor of telomeric silencing-1-like (DOT1L), the only known histone methyl transferase capable to produce H3K79 mono, di and tri-methylation, modulates ERα actions in hormone-responsive BC. Considering this evidence, ERα-DOT1L association was confirmed in ERα-positive OC cells, PEO1 and PEO4, by Co-IP. DOT1L pharmacological inhibition by EPZ004777 (EPZ) revealed the involvement of this epigenetic enzyme in cell proliferation, cell cycle progression and apoptosis. Transcriptome profiling after ICI (a Selective Estrogen Receptor Degrader) and EPZ treatment, in both cell lines, has underlined a deep impact of both compounds on ERα-modulated genes, including the down-regulation of ERα itself. On the other hand, functional analysis showed that commonly affected transcripts are involved in different cellular processes, such as cancer cell survival, chemoresistance and cell cycle progression. Moreover, ChIP-qPCR performed on ERα promoter highlighted ERα and DOT1L co-localization, both in PEO1 and in PEO4 cells, which was reduced after EPZ treatment, suggesting a role of this complex on receptor transcriptional activity. In addition, drug combination studies performed with EPZ and ICI showed an additive effect in cell growth inhibition. Taken together, these results suggest DOT1L as a potential therapeutic target in the treatment of OC.
2019-11-04 | E-MTAB-8198 | biostudies-arrayexpress
Project description:We used microarrays to detail the global transcriptional response mediated by ERalpha or ERbeta to the phytoestrogen genistein in the MCF-7 human breast cancer cell model. Experiment Overall Design: MCF-7 human breast cancer cells expressing endogenouse Estrogen Receptor Alpha (ERalpha) were infected with adenovirus carrying either estrogen receptor beta (AdERb) or no insert (Ad) at multiplicity of infection (moi) of 20. Cells were then treated with either vehicle control (veh), 6nM 17beta-estradiol (E2), 6nM genistein (LG), 300nM genistein (HG), 300nM S-Equol (EQ), HG+3uM ICI182,780 (IG), EQ+3uM ICI 182,780(IE) for a additional periods of 4h or 24hr before RNA extraction and hybridization on Affymetrix microarrays. We sought to determine if genistein and S-Equol, phytoestrogens selective for the ERbeta can elicit transcriptional response distinctive from those mediated by the ERalpha.
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2008-06-09 | E-MEXP-1497 | biostudies-arrayexpress
Project description:Epigenetic and metabolic reprogrammings are implicated in cancer progression with unclear mechanisms. We report here that the histone methyltransferase NSD2 drives cancer cell and tumor resistance to therapeutics such as tamoxifen, doxorubicin, and radiation by reprogramming of glucose metabolism. NSD2 coordinately up-regulates expression of TIGAR, HK2 and G6PD and stimulates pentose phosphate pathway (PPP) production of NADPH for ROS reduction. We discover that elevated expression of TIGAR, previously characterized as a fructose-2,6-bisphosphatase, is localized in the nuclei of resistant tumor cells where it stimulates NSD2 expression and global H3K36me2 mark. Mechanistically, TIGAR interacts with the antioxidant regulator Nrf2 and facilitates chromatin assembly of Nrf2-H3K4me3 methylase MLL1 and elongating Pol-II, independent of its metabolic enzymatic activity. In human tumors, high levels of NSD2 correlate strongly with early recurrence and poor survival and are associated with nuclear-localized TIGAR. This study defines a nuclear TIGAR-mediated, epigenetic autoregulatory loop functioning in redox rebalance for resistance to tumor therapeutics. A total of 4 samples were analyzed in this study. The study included two cell lines, MCF7 and the tamoxifen-resistant subline TMR. Both were were cultured in medium containing vehicle control and/or 4-hydroxytamoxifen (Tam). The untreated MCF7 and TMR cell lines served as controls for the study.
2016-10-22 | E-GEOD-62613 | biostudies-arrayexpress
Project description:RNA-Seq of human breast cancer cells MCF7 and LCC2 treated with Tamoxifen; EPZ or DMSO
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Project description:Histone ChIPSeq of H3K79me2 before and after EPZ treatment in MCF7 breast cancer cells
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