Estrogen represses Tgfbr1 and Bmpr1a expression via estrogen receptor beta in MC3T3-E1 cells

AbstractMC3T3-E1 is a clonal pre-osteoblastic cell line derived from newborn mouse calvaria, which is commonly used in osteoblast studies. To investigate the effects of estrogen on osteoblasts, we treated MC3T3-E1 cells with various concentrations of estrogen and assessed their proliferation. Next, we performed RNA deep sequencing to investigate the effects on estrogen target genes. Bmpr1a and Tgfbr1, important participants in the TGF-beta signaling pathway, were down-regulated in our deep sequencing results. Bioinformatics analysis revealed that estrogen receptor response elements (EREs) were present in the Bmpr1a and Tgfbr1 promoters. Culturing the cells with the estrogen receptor (ER) alpha or beta antagonists 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP) or 4-[2-phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-alpha]pyrimidin-3-yl] phenol (PTHPP), respectively, demonstrated that ER beta is involved in the estrogen-mediated repression of Tgfbr1 and Bmpr1a.The chromatin immunoprecipitation (ChIP) results were consistent with the conclusion that E2 increased the binding of ER beta at the EREs located in the Tgfbr1 and Bmpr1a promoters. Our research provides new insight into the role of estrogen in bone metabolisms.

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Correction: Potential Role of Estrogen Receptor Beta as a Tumor Suppressor of Epithelial Ovarian Cancer

PLoS ONE ◽

10.1371/annotation/480acc26-456b-4e06-8cb6-2834bd6f5553 ◽

2013 ◽

Vol 8 (5) ◽

Author(s):

Carine Bossard ◽

Muriel Busson ◽

David Vindrieux ◽

FranÃ§oise Gaudin ◽

VÃ©ronique Machelon ◽

...

Keyword(s):

Ovarian Cancer ◽

Estrogen Receptor ◽

Tumor Suppressor ◽

Epithelial Ovarian Cancer ◽

Potential Role ◽

Estrogen Receptor Beta ◽

Receptor Beta ◽

Correction Potential

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Crucial role of high-mobility group box 2 in mouse ovarian follicular development through estrogen receptor beta

Histochemistry and Cell Biology ◽

10.1007/s00418-022-02074-4 ◽

2022 ◽

Author(s):

Yu Yamaguma ◽

Naohiro Sugita ◽

Narantsog Choijookhuu ◽

Koichi Yano ◽

Deokcheol Lee ◽

...

Keyword(s):

Estrogen Receptor ◽

Crucial Role ◽

Estrogen Receptor Beta ◽

High Mobility ◽

Follicular Development ◽

High Mobility Group ◽

Ovarian Follicular Development ◽

Receptor Beta

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TP53 Status as a Determinant of Pro- vs Anti-Tumorigenic Effects of Estrogen Receptor-Beta in Breast Cancer

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djz051 ◽

2019 ◽

Vol 111 (11) ◽

pp. 1202-1215 ◽

Cited By ~ 9

Author(s):

Utpal K Mukhopadhyay ◽

Chetan C Oturkar ◽

Christina Adams ◽

Nadi Wickramasekera ◽

Sanjay Bansal ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Target Genes ◽

Molecular Taxonomy ◽

Estrogen Receptor Beta ◽

Control Group ◽

Wild Type ◽

International Consortium ◽

Tp53 Status ◽

Receptor Beta

Abstract Background Anti-tumorigenic vs pro-tumorigenic roles of estrogen receptor-beta (ESR2) in breast cancer remain unsettled. We investigated the potential of TP53 status to be a determinant of the bi-faceted role of ESR2 and associated therapeutic implications for triple negative breast cancer (TNBC). Methods ESR2-TP53 interaction was analyzed with multiple assays including the in situ proximity ligation assay. Transcriptional effects on TP53-target genes and cell proliferation in response to knocking down or overexpressing ESR2 were determined. Patient survival according to ESR2 expression levels and TP53 mutation status was analyzed in the basal-like TNBC subgroup in the Molecular Taxonomy of Breast Cancer International Consortium (n = 308) and Roswell Park Comprehensive Cancer Center (n = 46) patient cohorts by univariate Cox regression and log-rank test. All statistical tests are two-sided. Results ESR2 interaction with wild-type and mutant TP53 caused pro-proliferative and anti-proliferative effects, respectively. Depleting ESR2 in cells expressing wild-type TP53 resulted in increased expression of TP53-target genes CDKN1A (control group mean [SD] = 1 [0.13] vs ESR2 depletion group mean [SD] = 2.08 [0.24], P = .003) and BBC3 (control group mean [SD] = 1 [0.06] vs ESR2 depleted group mean [SD] = 1.92 [0.25], P = .003); however, expression of CDKN1A (control group mean [SD] = 1 [0.21] vs ESR2 depleted group mean [SD] = 0.56 [0.12], P = .02) and BBC3 (control group mean [SD] = 1 [0.03] vs ESR2 depleted group mean [SD] = 0.55 [0.09], P = .008) was decreased in cells expressing mutant TP53. Overexpressing ESR2 had opposite effects. Tamoxifen increased ESR2-mutant TP53 interaction, leading to reactivation of TP73 and apoptosis. High levels of ESR2 expression in mutant TP53-expressing basal-like tumors is associated with better prognosis (Molecular Taxonomy of Breast Cancer International Consortium cohort: log-rank P = .001; hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.84, univariate Cox P = .02). Conclusions TP53 status is a determinant of the functional duality of ESR2. Our study suggests that ESR2-mutant TP53 combination prognosticates survival in TNBC revealing a novel strategy to stratify TNBC for therapeutic intervention potentially by repurposing tamoxifen.

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Potential Role of Estrogen Receptor Beta as a Tumor Suppressor of Epithelial Ovarian Cancer

PLoS ONE ◽

10.1371/journal.pone.0044787 ◽

2012 ◽

Vol 7 (9) ◽

pp. e44787 ◽

Cited By ~ 60

Author(s):

Carine Bossard ◽

Muriel Busson ◽

David Vindrieux ◽

Françoise Gaudin ◽

Véronique Machelon ◽

...

Keyword(s):

Ovarian Cancer ◽

Estrogen Receptor ◽

Tumor Suppressor ◽

Epithelial Ovarian Cancer ◽

Potential Role ◽

Estrogen Receptor Beta ◽

Receptor Beta

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Expression of estrogen receptor beta isoforms in pancreatic adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.337 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 337-337

Author(s):

Mamoun Younes ◽

Charles J Ly ◽

Kanchan Singh ◽

Atilla Ertan ◽

Sushovan Guha ◽

...

Keyword(s):

Estrogen Receptor ◽

Pancreatic Adenocarcinoma ◽

Estrogen Receptor Status ◽

Estrogen Receptor Beta ◽

Small Series ◽

Clinicopathologic Factors ◽

Pn Stage ◽

Tamoxifen Efficacy ◽

Er Alpha ◽

Receptor Beta

337 Background: There have been several limited trials in which tamoxifen efficacy was tested in patients with pancreatic adenocarcinoma (PAC). Most of these studies were small series of patients with unresectable PAC and reported mixed results. In these studies, patients were not stratified by estrogen receptor status because estrogen receptor beta (ER-b) had not yet been identified, and PAC did not express the traditional ER-alpha. Recent studies showed that the effects of estrogens, phytoestrogens and tamoxifen on PAC cell lines depended on ER-b expression. The aim of this study was to investigate ER-b expression in human PAC and whether such expression correlates with any clinicopathologic parameters. Methods: Sections of tissue microarray containing 18 formalin fixed and paraffin embedded human PAC were stained by immunohistochemistry (IHC) using monoclonal antibodies to ER-b isoforms 1, 2, and 5 (ER-b1, ER-b2, and ER-b5, respectively), and for Cyclin A. The levels of ER-b isoform expression in tumor cells and the S-phase fraction (SPF) were determined using a quantitative digital image analysis solution (OTMIAS). Results: All isoforms were expressed in PAC, although at different levels. Higher mean ER-b2 levels correlated with male sex (p = 0.057), older age (p = 0.005), and lower pT stage (p = 0.008), but not with grade, pN stage, or SPF. Mean ER-b5 levels correlated negatively with SPF (p = 0.021), but not with sex, age, grade, pT or pN. Mean ER-b1 expression did not correlate with any of the above mentioned clinicopathologic factors. Conclusions: ER-b1, ER-b2, and ER-b5 are expressed in PAC. Higher ER-b2 and ER-b5 levels of expression are significantly correlated with lower tumor pT stage and with lower SPF, respectively, suggesting that they may play a tumor suppressive role in PAC. The association between ER-b2 levels and patient sex and age suggest that it could be influenced by endogenous/exogenous hormonal exposure.

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