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Agonists and knockdown of estrogen receptor ? differentially affect invasion of triple-negative breast cancer cells in vitro.

ABSTRACT: Estrogen receptor ? (ER?) is expressed in the majority of invasive breast cancer cases, irrespective of their subtype, including triple-negative breast cancer (TNBC). Thus, ER? might be a potential target for therapy of this challenging cancer type. In this in vitro study, we examined the role of ER? in invasion of two triple-negative breast cancer cell lines.MDA-MB-231 and HS578T breast cancer cells were treated with the specific ER? agonists ERB-041, WAY200070, Liquiritigenin and 3?-Adiol. Knockdown of ER? expression was performed by means of siRNA transfection. Effects on cellular invasion were assessed in vitro by means of a modified Boyden chamber assay. Transcriptome analyses were performed using Affymetrix Human Gene 1.0 ST microarrays. Pathway and gene network analyses were performed by means of Genomatix and Ingenuity Pathway Analysis software.Invasiveness of MBA-MB-231 and HS578T breast cancer cells decreased after treatment with ER? agonists ERB-041 and WAY200070. Agonists Liquiritigenin and 3?-Adiol only reduced invasion of MDA-MB-231 cells. Knockdown of ER? expression increased invasiveness of MDA-MB-231 cells about 3-fold. Transcriptome and pathway analyses revealed that ER? knockdown led to activation of TGF? signalling and induced expression of a network of genes with functions in extracellular matrix, tumor cell invasion and vitamin D3 metabolism.Our data suggest that ER? suppresses invasiveness of triple-negative breast cancer cells in vitro. Whether ER? agonists might be useful drugs in the treatment of triple-negative breast cancer, has to be evaluated in further animal and clinical studies.

SUBMITTER: Schuler-Toprak S

PROVIDER: S-EPMC5178087 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro.

Schüler-Toprak Susanne S Häring Julia J Inwald Elisabeth C EC Moehle Christoph C Ortmann Olaf O Treeck Oliver O

BMC cancer 20161221 1

<h4>Background</h4>Estrogen receptor β (ERβ) is expressed in the majority of invasive breast cancer cases, irrespective of their subtype, including triple-negative breast cancer (TNBC). Thus, ERβ might be a potential target for therapy of this challenging cancer type. In this in vitro study, we examined the role of ERβ in invasion of two triple-negative breast cancer cell lines.<h4>Methods</h4>MDA-MB-231 and HS578T breast cancer cells were treated with the specific ERβ agonists ERB-041, WAY20007 ...[more]

PMID: 28003019

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Project description:Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.

Project description:Estrogens have many beneficial effects in the brain. Previously, we evaluated the effects of two models of menopause (surgical vs. transitional) on multiple monoaminergic endpoints in different regions of the adult rat brain in comparison with levels in gonadally intact rats. Here we evaluated the effects of estrogen receptor (ER) agonist treatments in these same two models of menopause. Neurochemical endpoints were evaluated in the hippocampus (HPC), frontal cortex (FCX), and striatum (STR) of adult ovariectomized (OVX) rats and in rats that underwent selective and gradual ovarian follicle depletion by daily injection of 4-vinylcyclohexene-diepoxide (VCD), after 1- and 6-weeks treatment with 17β-estradiol (E2), or with selective ERα (PPT), ERβ (DPN), or GPR30 (G-1) agonists. Endpoints included serotonin (5-HT) and 5-Hydroxyindoleacetic acid, dopamine (DA), 3,4-Dihydroxyphenylacetic acid and homovanillic acid, norepinephrine (NE) and epinephrine, as well as the amino acids tryptophan (TRP) and tyrosine (TYR). Significant differences between the models were detected. OVX rats were much more sensitive to ER agonist treatments than VCD-treated rats. Significant differences between brain regions also were detected. Within OVX rats, more agonist effects were detected in the HPC than in any other region. One interesting finding was the substantial decrease in TRP and TYR detected in the HPC and FCX in response to agonist treatments, particularly in OVX rats. This is on top of the substantial decreases in TRP and TYR previously reported one week after OVX or VCD-treatments in comparison with gonadally intact controls. Other interesting findings included increases in the levels of 5-HT, DA, and NE in the HPC of OVX rats treated with DPN, increases in DA detected in the FCX of OVX rats treated with any of the ER agonists, and increases in 5-HT and DA detected in the STR of OVX rats treated with E2. Many effects that were observed after 1-week of treatment were no longer observed after 6-weeks of treatment, demonstrating that effects were temporary despite continued agonist treatment. Collectively, the results demonstrate significant differences in the effects of ER agonists on monoaminergic endpoints in OVX vs. VCD-treated rats that also were brain region-specific and time dependent. The fact that agonist treatments had lesser effects in VCD treated rats than in OVX rats may help to explain reports of lesser effects of estrogen replacement on cognitive performance in women that have undergone transitional vs. surgical menopause.

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Agonists and knockdown of estrogen receptor ? differentially affect invasion of triple-negative breast cancer cells in vitro.

Publications

Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro.

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