The role of PARP-1 in estrogen-dependent transcription [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE166168 | GEO | 2021/10/13
REPOSITORIES: GEO
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Project description:Poly (ADP-ribose) polymerase-1 (PARP-1), a multifunctional chromatin-modulating protein, has gained considerable attention as a target for therapeutic inhibitors in breast cancers. Accumulating evidence suggests a pathological role for PARP-1 in breast cancer through its effects on the transcription of tumor-related genes. Here we report the role of PARP-1 in estrogen-dependent transcription in estrogen receptor alpha (ERα)-positive breast cancers. Global nuclear run-on and sequencing (GRO-seq) and RNA-seq analyses suggest that PARP-1 controls the expression of estrogen-regulated genes in ER-positive (ER+) MCF-7 breast cancer cells. Further, ChIP-seq analyses revealed that PARP-1 directly regulates the ligand-dependent binding of ERa and FoxA1 to a subset of its genomic binding sites. Finally, we uncovered that the expression levels of the PARP-1 and estrogen coregulated gene set are enriched in luminal molecular-subtype of breast tumors and high PARP-1 expression in ER+ cases correlates with poor survival. Additionally, treatment with PARP-1 selective inhibitors showed attenuated estrogen-dependent growth of ER+ breast cancer cells. Taken together, the current study suggests that PARP-1 regulates critical molecular pathways that underlie proliferation of ER+ breast cancer cells.
2021-10-13 | GSE173976 | GEO
Project description:Hormone therapy targeting estrogen receptor (ER) is the principal treatment for ER-positive breast cancers but many cancers develop resistance to anti-estrogens. Cyclin-dependent kinase 8 (CDK8) is a transcriptional regulator of several oncogenic pathways. Expression levels of CDK8 and ERα are inversely correlated in breast cancers suggesting a functional association between CDK8 and ER. CDK8 inhibition by selective small-molecule inhibitors, by shRNA knockdown or by CRISPR-Cas9 knockout suppressed estrogen-induced transcription, with no significant effects on ERα protein expression or phosphorylation. CDK8 inhibition also abrogated the mitogenic effect of estrogen on ER-positive breast cancer cells and potentiated growth inhibition by the ER antagonist fulvestrant. In vivo, administration of a CDK8 inhibitor suppressed ER-positive breast cancer xenograft growth and augmented the effects of fulvestrant with no apparent toxicity. CDK8 inhibitors also suppressed the development of estrogen independence in ER-positive breast cancer cells. These results identify CDK8 as a novel drug target for breast cancer therapy.
2017-02-14 | GSE93193 | GEO
Project description:Breast tumors are characterized into different subtypes based on their surface marker expression, which affects their prognosis and treatment. For example, triple negative breast cancer cells (ER-/PR-/Her2-) show reduced susceptibility towards radiotherapy and chemotherapeutic agents. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in clinical trials, both as single agents and in combination with other chemotherapeutics, in several subtypes of breast cancer patients. PARP1 is involved in DNA repair, apoptosis, and transcriptional regulation and an understanding of the effects of PARP inhibitors, specifically on metabolism, is currently lacking. Here, we have used NMR-based metabolomics to probe the cell line-specific effects of PARP inhibitor and radiation on metabolism in three distinct breast cancer cell lines. Our data reveal several cell line independent metabolic changes upon PARP inhibition, including an increase in taurine. Pathway enrichment and topology analysis identified that nitrogen metabolism, glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis and taurine and hypotaurine metabolism were enriched after PARP inhibition in the three breast cancer cell lines. We observed that the majority of metabolic changes due to radiation as well as PARP inhibition were cell line dependent, highlighting the need to understand how these treatments affect cancer cell response via changes in metabolism. Finally, we observed that both PARP inhibition and radiation induced a similar metabolic response in the HCC1937 (BRCA mutant cell line), but not in MCF-7 and MDAMB231 cells, suggesting that radiation and PARP inhibition share similar interactions with metabolic pathways in BRCA mutant cells. Our study emphasizes the importance of differences in metabolic responses to cancer treatments in different subtypes of cancers.
2016-11-07 | MTBLS337 | MetaboLights
Project description:More than two thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER- breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild type for p53. Despite harboring wild type p53, ER+ breast cancer cells are resistant to chemotherapy-induced apoptosis in the presence of estrogen. Using genome-wide approaches we have addressed the mechanism by which ER antagonizes the pro-apoptotic function of p53. Interestingly both ER agonists such as estradiol and selective ER modulators (SERM) such as tamoxifen promote p53 antagonism. In contrast the full ER antagonist fulvestrant blocks the ability of ER to inhibit p53-mediated cell death. This suggests an improved strategy for the treatment of ER+ breast cancer utilizing antagonists that completely block ER action together with drugs that activate p53-mediated cell death. MCF7 cells were hormone-depleted for 3 days and then treated with 10 uM doxorubicin for 12 hours
2012-11-02 | E-GEOD-39870 | biostudies-arrayexpress
Project description:More than two thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER- breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild type for p53. Despite harboring wild type p53, ER+ breast cancer cells are resistant to chemotherapy-induced apoptosis in the presence of estrogen. Using genome-wide approaches we have addressed the mechanism by which ER antagonizes the pro-apoptotic function of p53. Interestingly both ER agonists such as estradiol and selective ER modulators (SERM) such as tamoxifen promote p53 antagonism. In contrast the full ER antagonist fulvestrant blocks the ability of ER to inhibit p53-mediated cell death. This suggests an improved strategy for the treatment of ER+ breast cancer utilizing antagonists that completely block ER action together with drugs that activate p53-mediated cell death.
2012-11-02 | GSE39870 | GEO
Project description:Estrogen receptor positive breast cancer is the most prevalent form of breast cancer. Although a number of available drugs are highly effective at blocking estrogen mediated receptor activity, thousands of patients die every year from ER positive breast cancers because the disease progresses to a stage at which these drugs are no longer effective. Thus, it is crucial to establish a comprehensive understanding of the biology of the estrogen receptor (ER) in ER:positive breast cancers that progress despite hormone therapy, a gap in knowledge that remains a serious impediment to successful treatment of patients with ER positive breast cancer. A key question that must be answered is how the estrogen receptor retains the capacity to activate transcription in the absence or near absence of estrogen. We have found a partial answer to this question upon investigating the effect of amplification and overexpression of Wolf Hirschhorn Syndrome Candidate 1:Like 1 (WHSC1L1), a gene that is amplified in 15% of breast cancers that codes for a histone:lysine methyltransferase. WHSC1L1 lies in the 8p11:p12 amplicon, a region of gene amplification that is strongly associated with breast cancer. In this study, we performed shRNA knockdown of the catalytically inactive short isoform of WHSC1L1 in SUM44PE breast cancer cells and found that expression of the short isoform of WHSC1L1 is necessary for expression of the estrogen receptor in this highly ER:positive cell line. In addition, we found that the estrogen receptor binds chromatin extensively in the absence of exogenous estrogen, including several actively transcribed canonical ER target genes, indicating that estrogen receptor signaling is active in SUM44 cells in estrogen free conditions. These findings represent a novel model for ER biology in luminal B breast cancers harboring amplification of WHSC1L1 and provide insight into the mechanisms by which ER: positive breast cancers become unresponsive to SERMs or aromatase inhibitors.
2016-05-07 | E-MTAB-3739 | biostudies-arrayexpress
Project description:Estrogen Receptor-a (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3a), but mechanistic insight is lacking. We now show that FOXA1 is the defining factor that governs differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 dictates genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells is sufficient to alter ER binding and response to endocrine treatment. As such, FOXA1 is the primary determinant that regulates estrogen-ER activity and endocrine response in breast cancer cells and is sufficient to program ER functionality in non-breast cancer contexts. breast cancer MCF-7 cell lines were treaated in the presence of Estrogen, Estrogen plus Tamoxifen, Tamoxifen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen or 1 microM Tamoxifen for 6 h. There were four biological replicates for each of the four different groups.
2010-11-17 | E-GEOD-25314 | biostudies-arrayexpress
Project description:Limited knowledge of the changes in estrogen receptor (ER) signaling during the transformation of the normal mammary gland to breast cancer hinders the development of effective prevention and treatment strategies. Differences in estrogen signaling between normal human primary breast epithelial cells and primary breast tumors obtained immediately following surgical excision were explored. Transcriptional profiling of normal ER+ mature luminal mammary epithelial cells and ER+ breast tumors revealed significant difference in the response to estrogen stimulation. Consistent with these differences in gene expression, the normal and tumor ER cistromes were distinct and sufficient to segregate normal breast tissues from breast tumors. The selective enrichment of the DNA binding motif GRHL2 in the breast cancer-specific ER cistrome suggests that it may play a role in the differential function of ER in breast cancer. Depletion of GRHL2 resulted in altered ER binding and differential transcriptional responses to estrogen stimulation. Furthermore, GRHL2 was demonstrated to be essential for estrogen-stimulated proliferation of ER+ breast cancer cells. DLC1 was also identified as an estrogen-induced tumor suppressor in the normal mammary gland with decreased expression in breast cancer. In clinical cohorts, loss of DLC1 and gain of GRHL2 expression are associated with breast cancer and are independently predictive for worse survival. This study suggests that normal ER signaling is lost and tumor-specific ER signaling is gained during breast tumorigenesis. Unraveling these changes in ER signaling during breast cancer progression should aid the development of more effective prevention strategies and targeted therapeutics. SIGNIFICANCE STATEMENT: Abnormal estrogen receptor (ER) signaling drives the majority of breast cancers and is targeted by endocrine therapies. However, in normal breast tissue, ER signaling has been demonstrated to promote benign functions such as development and differentiation. Using genomic techniques to characterize ER function in normal breast and breast tumors, this study reveals differential patterns of ER signaling, suggesting that normal ER signaling is lost and tumorigenic ER signaling gained during breast tumor formation. Better understanding of this process can aid the development of improved breast cancer prevention strategies and therapies.
2019-05-27 | GSE99680 | GEO
Project description: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.
2024-07-03 | GSE268001 | GEO
Project description:Estrogen Receptor-a (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3a), but mechanistic insight is lacking. We now show that FOXA1 is the defining factor that governs differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 dictates genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells is sufficient to alter ER binding and response to endocrine treatment. As such, FOXA1 is the primary determinant that regulates estrogen-ER activity and endocrine response in breast cancer cells and is sufficient to program ER functionality in non-breast cancer contexts. FoxA1 silenced breast cancer MCF-7 cell lines or control siRNA in the presence of Estrogen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen for 6 h. There were three biological replicates for each of the four different groups.
2010-11-17 | E-GEOD-25315 | biostudies-arrayexpress