Estrogen receptor α promotes breast cancer by reprogramming cell metabolism
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE74034 | GEO | 2016/10/12
SECONDARY ACCESSION(S): PRJNA298774
REPOSITORIES: GEO
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Project description:Estrogen receptor α (ERα) is a key regulator of breast growth and breast cancer development. However, the role of ERα in metabolic reprogramming, a hallmark of cancer, is not well documented. In this study, using an integrated approach combining genome-wide mapping of chromatin bound ERα with estrogen induced transcript and metabolic profiling, we demonstrate that ERα reprograms metabolism upon estrogen stimulation, including changes in aerobic glycolysis, nucleotide and amino acid synthesis, and choline metabolism. We show, for the first time, that the ERα target gene choline phosphotransferase 1 (CHPT1) plays an essential role in estrogen induced increases in phosphatidylcholine (PtdCho) levels and that CHPT1 promotes tumorigenesis and proliferation. Furthermore, we show that CHPT1 is overexpressed in tumors compared to normal breast. We also demonstrate that ERα promotes aerobic glycolysis through increased expression of glycolytic genes. In conclusion, this study highlights the importance of ERα for metabolic alterations in breast cancer cells. Furthermore, overexpression of the ERα target CHPT1 in breast cancer supports its potential as a therapeutic target.
2016-10-12 | GSE74033 | GEO
Project description:Estrogen receptor α (ERα) is a key regulator of breast growth and breast cancer development. However, the role of ERα in metabolic reprogramming, a hallmark of cancer, is not well documented. In this study, using an integrated approach combining genome-wide mapping of chromatin bound ERα with estrogen induced transcript and metabolic profiling, we demonstrate that ERα reprograms metabolism upon estrogen stimulation, including changes in aerobic glycolysis, nucleotide and amino acid synthesis, and choline metabolism. We show, for the first time, that the ERα target gene choline phosphotransferase 1 (CHPT1) plays an essential role in estrogen induced increases in phosphatidylcholine (PtdCho) levels and that CHPT1 promotes tumorigenesis and proliferation. Furthermore, we show that CHPT1 is overexpressed in tumors compared to normal breast. We also demonstrate that ERα promotes aerobic glycolysis through increased expression of glycolytic genes. In conclusion, this study highlights the importance of ERα for metabolic alterations in breast cancer cells. Furthermore, overexpression of the ERα target CHPT1 in breast cancer supports its potential as a therapeutic target.
2016-10-12 | GSE74032 | GEO
Project description:Estrogen receptor α promotes breast cancer by reprogramming cell metabolism
| PRJNA298774 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-03-02 | E-GEOD-53533 | biostudies-arrayexpress
Project description:Estrogen drives both transcriptional activation and proteolysis of estrogen receptor alpha (ER alpha; encoded by ESR1). Here we observed variable and overlapping ESR1 mRNA levels in 200 ER alpha-negative and 50 ER alpha-positive primary breast cancers examined, which suggests important posttranscriptional ER alpha regulation. Our results indicate that Src cooperates with estrogen to activate ER alpha proteolysis. Inducible Src stimulated ligand-activated ER alpha transcriptional activity and reduced ER alpha t(1/2). Src and ER alpha levels were inversely correlated in primary breast cancers. ER alpha-negative primary breast cancers and cell lines showed increased Src levels and/or activity compared with ER alpha-positive cancers and cells. ER alpha t(1/2) was reduced in ER alpha-negative cell lines. In both ER alpha-positive and -negative cell lines, both proteasome and Src inhibitors increased ER alpha levels. Src inhibition impaired ligand-activated ER alpha ubiquitylation and increased ER alpha levels. Src siRNA impaired ligand-activated ER alpha loss in BT-20 cells. Pretreatment with Src increased ER alpha ubiquitylation and degradation in vitro. These findings provide what we believe to be a novel link between Src activation and ER alpha proteolysis and support a model whereby crosstalk between liganded ER alpha and Src drives ER alpha transcriptional activity and targets ER alpha for ubiquitin-dependent proteolysis. Oncogenic Src activation may promote not only proliferation, but also estrogen-activated ER alpha loss in a subset of ER alpha-negative breast cancers, altering prognosis and response to therapy.
| S-EPMC1906730 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-09-15 | GSE210608 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-09-15 | GSE232389 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-01-11 | GSE93881 | GEO
Project description:Breast cancer is the most commonly diagnosed malignancy in female worldwide, over 70% of which are estrogen receptor α (ERα) positive. ERα has a crucial role in the initiation and progression of breast cancer and is an indicator of endocrine therapy, while endocrine resistance is an urgent problem in ER-positive breast cancer patients. In the present study, we identify a novel E3 ubiquitin ligase TRIM11 function to facilitate ERα signaling. TRIM11 is overexpressed in human breast cancer, and associates with poor prognosis. The protein level of TRIM11 is highly correlated with ERα. RNA-seq results suggest that ERα signaling may be an underlying target of TRIM11. Depletion of TRIM11 in breast cancer cells significantly decreases cell proliferation and migration. And the suppression effects can be reversed by overexpressing ERα. In addition, ERα protein level, ERα target genes expression and estrogen response element activity are also dramatically decreased by TRIM11 depletion. Further mechanistic analysis indicates that the RING domain of TRIM11 interacted with the N terminal of ERα in the cytoplasm and promotes its mono-ubiquitination, thus enhances ERα protein stability. Our study describes TRIM11 as a modulating factor of ERα and increases ERα stability via mono-ubiquitination. TRIM11 could be a promising therapeutic target for breast cancer treatment.
| S-EPMC7326724 | biostudies-literature
Project description:Estrogen receptor α is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. In our study, we identified the novel E3 ubiquitin ligase SHARPIN function to facilitate ERα signaling. SHARPIN is highly expressed in human breast cancer and correlates with ERα protein level by immunohistochemistry. SHARPIN expression level correlates with poor prognosis in ERα positive breast cancer patients. SHARPIN depletion based RNA-sequence data shows that ERα signaling is a potential SHARPIN target. SHARPIN depletion significantly decreases ERα protein level, ERα target genes expression and estrogen response element activity in breast cancer cells, while SHARPIN overexpression could reverse these effects. SHARPIN depletion significantly decreases estrogen stimulated cell proliferation in breast cancer cells, which effect could be further rescued by ERα overexpression. Further mechanistic study reveals that SHARPIN mainly localizes in the cytosol and interacts with ERα both in the cytosol and the nuclear. SHARPIN regulates ERα signaling through protein stability, not through gene expression. SHARPIN stabilizes ERα protein via prohibiting ERα protein poly-ubiquitination. Further study shows that SHARPIN could facilitate the mono-ubiquitinaiton of ERα at K302/303 sites and facilitate ERE luciferase activity. Together, our findings propose a novel ERα modulation mechanism in supporting breast cancer cell growth, in which SHARPIN could be one suitable target for development of novel therapy for ERα positive breast cancer.
| S-EPMC5652769 | biostudies-literature