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DREAM On, DREAM Off: A Review of the Estrogen Paradox

ABSTRACT: It is generally assumed that all estrogen receptor positive (ER+) breast cancers proliferate in response to estrogen and therefore examples of estrogen-induced regression of ER+ cancers are paradoxical. This review reexamines the estrogen regression paradox for the Luminal A subtype of ER+ breast cancers. The proliferative response to estrogen is shown to depend on the level of ER. Mechanistically, a window of opportunity study of pre-operative estradiol suggested that with higher levels of ER, estradiol could activate the DREAM-MMB (Dimerization partner, Retinoblastoma-like proteins, E2F4, and MuvB – MYB-MuvB) pathway to decrease proliferation. The response of breast epithelium and the incidence of breast cancers during hormonal variations that occur during the menstrual cycle and at the menopausal transition respectively suggest that a single hormone, either estrogen, progesterone or androgen could activate the DREAM pathway leading to reversible cell cycle arrest. Conversely, the presence of two hormones, could switch the DREAM-MMB complex to a pro-proliferative pathway. Using publicly available data, we examine the gene expression changes after aromatase inhibitors and ICI 182,780 to provide support for the hypothesis. This review suggests that it might be possible to integrate all current hormonal therapies for Luminal A tumors within a single theoretical schema.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268001 | GEO | 2024/07/03

REPOSITORIES: GEO

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DREAM, a Possible Answer to the Estrogen Paradox of the Women’s Health Initiative Trial

Project description:Estrogen is thought to cause proliferation of all estrogen receptor positive (ER+) breast cancers. Paradoxically, in the Women’s Health Initiative Trial, estrogen-only hormone replacement therapy reduced the incidence and mortality of low grade, ER+, HER2- breast cancer. We gave estradiol to 19 post-menopausal women with newly diagnosed low-grade, ER+, HER2- breast cancer in a prospective window of opportunity clinical trial and examined the changes in proliferation and gene expression before and after estradiol treatment. Ki67 decreased in 13/19 (68%) patients and 8/13 (62%) showed a decrease in Risk of Recurrence Score. We chose three prototypical estrogen responders (greatest decrease in ROR) and non-responders (no/minimal change in ROR) and applied a differential gene expression analysis to develop pre-treatment (PRESTO-30core) and post-treatment (PRESTO-45surg) gene expression profiles. The PRESTO-30core predicted adjuvant benefit in a published series of tamoxifen, the partial estrogen agonist. Of the 45 genes in the PRESTO-45surg, thirty contain the Cell cycle genes Homology Region (CHR) motif that binds the class B multi-vulva complex (MuvB) a member of the DREAM (Dimerization partner, retinoblastoma-like proteins, E2F, MuvB) complex responsible for reversible cell cycle arrest or quiescence. There was also near uniform suppression (89%) of the remaining DREAM genes consistent with estrogen induced activation of the DREAM complex to mediate cell cycle block after a short course of estrogens. To our knowledge, this is the first report to show hormonal modulation of DREAM genes and suggest involvement of DREAM pathway associated quiescence in endocrine responsive post-menopausal ER+ breast cancers.

2021-12-27 | GSE139688 | GEO

Drosophila Myb-MuvB/dREAM (ChIP-chip data)

2007-11-14 | GSE9087 | GEO

Drosophila Myb-MuvB/dREAM (Expression data)

Project description:Myb-MuvB (MMB)/dREAM is a nine subunit complex first described in Drosophila as a repressor of transcription, dependent upon E2F2 and the RBFs. Myb, an integral member of MMB, curiously plays no role in the silencing of the test genes previously analyzed. Moreover, Myb plays an activating role in DNA replication in Drosophila egg chamber follicle cells. The essential functions for Myb are executed as part of MMB. This duality of function lead to the hypothesis that MMB, which contains both known activator and repressor proteins, might function as part of a switching mechanism that is dependent upon DNA sites and developmental context. Here, we used proliferating Drosophila Kc tissue culture cells to explore both the network of genes regulated by MMB (employing RNAi and micro-array expression analysis) and the genomic locations of MMB following chromatin immunoprecipitation (ChIP) and tiling array analysis. MMB occupies thousands of chromosomal sites where a substantial number are proximal to repressed genes that are normally expressed in a wide range of developmental pathways. At many of these sites, E2F2 was critical for repression whereas at other non-overlapping sites, Myb was critical for repression. These data highlight that the MMB factors are utilized in a combinatorial way for targeting gene regulation. We also found sites where MMB was a positive regulator of transcript levels that included genes required for mitotic functions (G2/M), which may explain some of the chromosome instability phenotypes attributed to loss of Myb function in myb mutants. Keywords: Drosophila Myb-MuvB/dREAM, RNAi, ChIP-chip

2007-11-14 | GSE8751 | GEO

Transcription profiling of Drosophila Myb-MuvB/dREAM

Project description:Myb-MuvB (MMB)/dREAM is a nine subunit complex first described in Drosophila as a repressor of transcription, dependent upon E2F2 and the RBFs. Myb, an integral member of MMB, curiously plays no role in the silencing of the test genes previously analyzed. Moreover, Myb plays an activating role in DNA replication in Drosophila egg chamber follicle cells. The essential functions for Myb are executed as part of MMB. This duality of function lead to the hypothesis that MMB, which contains both known activator and repressor proteins, might function as part of a switching mechanism that is dependent upon DNA sites and developmental context. Here, we used proliferating Drosophila Kc tissue culture cells to explore both the network of genes regulated by MMB (employing RNAi and micro-array expression analysis) and the genomic locations of MMB following chromatin immunoprecipitation (ChIP) and tiling array analysis. MMB occupies thousands of chromosomal sites where a substantial number are proximal to repressed genes that are normally expressed in a wide range of developmental pathways. At many of these sites, E2F2 was critical for repression whereas at other non-overlapping sites, Myb was critical for repression. These data highlight that the MMB factors are utilized in a combinatorial way for targeting gene regulation. We also found sites where MMB was a positive regulator of transcript levels that included genes required for mitotic functions (G2/M), which may explain some of the chromosome instability phenotypes attributed to loss of Myb function in myb mutants. Experiment Overall Design: RNAi to deplete Lin-52, Mip40, Myb, Mip120, Mip130, E2F2, both RBFs (RBF1 and RBF2) and L(3)MBT were performed in triplicate. RNAi with a nonspecific RNA derived from a pBSK+ plasmid (named SK+) was used as control. Total RNA was extracted from RNAi-transfected cells after 4 days using RNeasy Mini Kit (QIAGEN).

2008-06-16 | E-GEOD-8751 | biostudies-arrayexpress

Drosophila Myb-MuvB/dREAM

Project description:Drosophila Myb-MuvB/dREAM

| PRJNA102609 | ENA

DREAM Interrupted: Severing LIN-35-MuvB association in Caenorhabditis elegans impairs DREAM function but not its chromatin localization

Project description:The highly conserved DREAM transcriptional repressor complex contains an RB-like pocket protein, an E2F-DP transcription factor heterodimer, and the 5-subunit MuvB complex. Using CRISPR/Cas9 targeted mutagenesis, we disrupted the interaction between the sole Caenorhabditis elegans pocket protein LIN-35 and the MuvB subunit LIN-52. A triple alanine substitution of LIN-52's LxCxE motif (3A) severed LIN-35-MuvB association and caused classical DREAM mutant phenotypes, including synthetic multiple vulvae, high-temperature arrest, and ectopic expression of germline genes in the soma. We performed RNA-seq in lin-52(3A) mutant late embryos (4 replicates) compared to lin-52(WT) wild-type late embryos (4 replicates) to assess the genome-wide effects on gene expression that result from severing LIN-35-MuvB association.

2022-05-24 | GSE199287 | GEO

Structure and molecular assembly of a MuvB transcription factor complex with the nucleosome

Project description:The core cell cycle machinery genes are transcriptionally regulated by the MuvB family of protein complexes in a cell cycle specific manner. During cell cycle exit in quiescence or senescence, the DREAM complex, which is the repressive form of MuvB, directs transcriptional repression of cell cycle genes; conversely during cell proliferation, the complex of MuvB with the transcription factors (TFs) B-MYB and FOXM1 activate mitotic genes during the G2 phase of the cell cycle. The mechanisms of transcriptional regulation of these complexes are still poorly characterised. Here we combine biochemical analysis and in vitro reconstitution, with structural analysis by cryo-electron microscopy (cryo-EM) and cross-linking mass spectrometry (XL-MS), to functionally examine these complexes. Our data suggests that MuvB is a chromatin regulator whereby a core region binds the nucleosome and remodels it, thereby exposing nucleosomal DNA. This remodelling activity is supported by B-MYB which directly binds the remodelled DNA. Given the remodelling activity on the nucleosome, we propose that the MuvB complex with B-MYB (MMB) function as a pioneer transcription factor complex. Our data rationalises prior biochemical and cellular studies and provides a molecular framework of interactions on a protein complex, which is key for cell cycle regulation.

2022-08-17 | PXD031421 | Pride

DREAM represses distinct targets by cooperating with different THAP domain proteins [RNA-seq]

Project description:The DREAM (DP, Retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell cycle and other genes, but its mechanism of action is unclear. Here we demonstrate that two C. elegans THAP domain proteins, LIN-15B and LIN-36, co-localize with DREAM and function by different mechanisms for repression of distinct sets of targets. LIN-36 represses classical cell cycle targets by promoting DREAM binding and gene body enrichment of H2A.Z. Furthermore, the function of DREAM subunit EFL-1/E2F is specific for LIN-36 targets. In contrast, LIN-15B represses a subset of germline targets by facilitating H3K9me2 promoter marking. In humans, THAP proteins have been implicated in cell cycle regulation by poorly understood mechanisms. We propose that THAP domain proteins are key mediators of Rb/DREAM function, facilitating repression of distinct sets of targets.

2020-08-13 | GSE155190 | GEO

DREAM represses distinct targets by cooperating with different THAP domain proteins [CHIP-seq]

2020-08-13 | GSE155189 | GEO

p21 Regulates Wnt-Notch Balance via DREAM/MMB/Rb-E2F1 and Maintains Intestinal Stem Cell Homeostasis

Project description:The crosstalk and balance regulation of Wnt-Notch have been known to be essential for cell fate decision and tissue regeneration, while how the balance is maintained and how the Wnt-Notch pathways are connected with the cell cycle regulation are still not clear. In the mouse model with accelerated aging phenotypes due to the loss of cell cycle inhibitor p21 function in Werner syndrome background, we observed the imbalance of Wnt-Notch signaling, along with the fast turnover of intestinal epithelia, which might cause the abnormal mobilization of stem cells, exhaust the stem cell reservoir, and result in the accelerated aging phenotypes. We revealed that the loss of p21 caused the shift of DREAM/Rb complex to MMB/E2F1 complex and the fast turnover of intestinal epithelia. Importantly, we identified the E2F1 as the transcriptional regulator for Notch1, which connected the p21-DREAM/MMB/Rb-E2F1 pathway with Wnt-Notch pathway. The overexpression of p21 rescued the imbalance of Wnt-Notch pathway. Our data identify p21 as an important factor in maintaining sequential mobilization, proliferation, and homeostasis of intestinal stem cells.

2023-12-10 | GSE248188 | GEO

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