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Estrogen Receptor Beta Impacts Hormone-Induced Alternative mRNA Splicing in Breast Cancer Cells

ABSTRACT: Estrogens play an important role in breast cancer (BC) development and progression, where the two isoforms of the estrogen receptor (ER? and ER?) are generally co-expressed and mediate the effects of these hormones in cancer cells. ER? has been suggested to exert an antagonist role toward the oncogenic activities of ER?, and for this reason it is considered an oncosuppressor. As clinical evidence regarding a prognostic role for this receptor subtype in hormone-responsive BC is still limited and conflicting, more knowledge is required on the biological functions of ER? in cancer cells. We described previously the ER? and ER? interactomes of BC cells, identifying specific and distinct patterns of protein interactions for the two receptors. In particular, we identified factors involved in mRNA splicing and maturation as important components of both ER? and ER? pathways. Guided by these findings, we investigated here in depth the differences in the early transcriptional events and RNA splicing patterns induced in ER? vs ER?+ER? cells, by expressing ER? in ER?+ human BC MCF-7 cells. High-throughput mRNA sequencing was then performed in both cell lines after stimulation with 17b-estradiol, and the results obtained were compared. We investigated here in depth the differences in the early transcriptional events and RNA splicing patterns induced in ER? vs ER?+ER? cells, by expressing ER? in ER?+ human BC MCF-7 cells. High-throughput mRNA sequencing was then performed in both cell lines after stimulation with 17b-estradiol, and the results obtained were compared.

ORGANISM(S): Homo sapiens

SUBMITTER: Antonio Rinaldi

PROVIDER: E-GEOD-64590 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Estrogen Receptor Beta Impacts Hormone-Induced Alternative mRNA Splicing in Breast Cancer Cells

Project description:Estrogens play an important role in breast cancer (BC) development and progression, where the two isoforms of the estrogen receptor (ERα and ERβ) are generally co-expressed and mediate the effects of these hormones in cancer cells. ERβ has been suggested to exert an antagonist role toward the oncogenic activities of ERα, and for this reason it is considered an oncosuppressor. As clinical evidence regarding a prognostic role for this receptor subtype in hormone-responsive BC is still limited and conflicting, more knowledge is required on the biological functions of ERβ in cancer cells. We described previously the ERβ and ERα interactomes of BC cells, identifying specific and distinct patterns of protein interactions for the two receptors. In particular, we identified factors involved in mRNA splicing and maturation as important components of both ERα and ERβ pathways. Guided by these findings, we investigated here in depth the differences in the early transcriptional events and RNA splicing patterns induced in ERα vs ERα+ERβ cells, by expressing ERβ in ERα+ human BC MCF-7 cells. High-throughput mRNA sequencing was then performed in both cell lines after stimulation with 17b-estradiol, and the results obtained were compared.

2015-09-01 | GSE64590 | GEO

Genome-wide copy number profiling of MCF-7 and fulvestrant-resistant MCF-7/FR cells by SNP microarray.

Project description:Estrogens have been shown to elicit anti-cancer effects against estrogen receptor alpha (ER)-positive breast cancer. We sought to determine the underlying mechanism of therapeutic response. Response to 17b-estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient-derived xenografts, C7-2-HI and C4-HI murine mammary adenocarcinomas, and long-term estrogen-deprived MCF-7 cells. As another means to reactivate ER, the anti-estrogen fulvestrant was withdrawn from fulvestrant-resistant MCF-7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17b-estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17b-estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anti-cancer effects were most evident in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long-term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17b-estradiol treatment and anti-estrogen withdrawal hyperactivate ER, which drives an unfolded protein response activation and subsequent growth inhibition and apoptosis. 17b-estradiol treatment should be considered as an alternative therapy for anti-estrogen-resistant disease, particularly in patients with tumors harboring ESR1 amplification or overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may enhance the therapeutic effects of ER reactivation.

2019-08-19 | GSE121631 | GEO

Fulvestrant withdrawal from fulvestrant-resistant MCF-7/FR cells

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GR and ER co-activation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome

Project description:Analysis of MCF-7 cells treated for 4h with Ethanol, Estradiol (E2), Dexamethasone (Dex), or Estradiol + Dexamethasone (E2 + Dex) In estrogen receptor (ER)-negative breast cancer (BC), high tumor glucocorticoid receptor (GR) expression has been associated with a relatively poor outcome. In contrast, using a meta-analysis of several genomic datasets, here we find that tumor GR mRNA expression is associated with improved ER+ relapse-free survival (RFS) (independently of progesterone receptor (PR) expression). To understand the mechanism by which GR expression is associated with a better ER+ BC outcome, the global effect of GR-mediated transcriptional activation in ER+ BC cells was studied. Analysis of GR chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in ER+/GR+ MCF-7 cells revealed that upon co-activation of GR and ER, GR chromatin association became enriched at proximal promoter regions. Furthermore, following ER activation, increased association of GR was observed at ER, FOXO, and AP1 response elements. In addition, it was determined that ER associated with GR response elements, suggesting that ER and GR interact in a complex. Co-activation of GR and ER resulted in increased expression (relative to ER activation alone) of transcripts that encode proteins promoting cellular differentiation (e.g. KDM4B, VDR) and inhibiting Wnt-signaling (IGFBP4). Finally, expression of these individual pro-differentiation genes was associated with significantly improved RFS in ER+ BC patients. Together, these data demonstrate that the co-expression and subsequent activity of tumor cell GR and ER contribute to the less aggressive natural history of early-stage BC by coordinating the altered expression of genes favoring differentiation. Four treatment samples (Vehicle V, Dex D, E2, or Dex+E2). Three biological replicate experiments per sample. Vehicle sample is Ethanol control.

2016-04-01 | E-GEOD-79761 | biostudies-arrayexpress

GR and ER co-activation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome

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The expression patterns of 17b-estradiol responsive genes in wt MCF7, OHT resistant MCF7 and ICI resistant MCF7

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2007-09-14 | GSE5840 | GEO

Transcription profiling of human MCF-7 cells treated with proteasome inhibitor MG132 and either dexamethasone or 17b-estradiol

Project description:The objective of the study was to investigate the effect of proteasome inhibition on glucocorticoid and estrogen receptor regulated gene expression. Experiment Overall Design: MCF-7 cells were treated with proteasome inhibitor (MG132), dexamethasone, 17b-estradiol or MG132 plus dexamethasone or MG132 plus 7b-estardiol. Control cells were not treated. RNA was collected from 2 biological experiments.

2008-06-20 | E-GEOD-8383 | biostudies-arrayexpress

Proteomic analysis of human mammospheres treated with lysine and estradiol

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2020-11-25 | PXD022008 | Pride

Transcription profiling of human wild type MCF7, OHT resistant MCF7 and ICI resistant MCF7 17b-estradiol responsive genes

Project description:Compare the expression pattern of 17b-estradiol responsive genes in parent, OHT-resistant and ICI-resistant breast cancer cells. Experiment Overall Design: Data for 4 replicate experiments performed with biologically independent samples. Experiment Overall Design: KN01M001v0 DMSO (control) wt MCF7 -> GSM136152 Experiment Overall Design: KN01H002v0 DMSO (control) wt MCF7 -> GSM136148 Experiment Overall Design: KN01H003v0 DMSO (control) wt MCF7 -> GSM136150 Experiment Overall Design: KN01H004v0 DMSO (control) wt MCF7 -> GSM136152 Experiment Overall Design: KN01M005v0 17b-estradiol (10nM 4h) wt MCF7 -> GSM136153 Experiment Overall Design: KN01H006v0 17b-estradiol (10nM 4h) wt MCF7 -> GSM136154 Experiment Overall Design: KN01H007v0 17b-estradiol (10nM 4h) wt MCF7 -> GSM136155 Experiment Overall Design: KN01H008v0 17b-estradiol (10nM 4h) wt MCF7 -> GSM136156

2008-06-14 | E-GEOD-5840 | biostudies-arrayexpress

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