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Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells

ABSTRACT: Our study reveals that while antiestrogen therapies effectively limit tumor growth in ER-positive breast cancers, they also trigger a transcriptional program that favors immune evasion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181909 | GEO | 2022/01/12

REPOSITORIES: GEO

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Estrogen deprivation triggers and immunosuppressive phenotype in breast cancer cells

Project description:Our study reveals that while antiestrogen therapies effectively limit tumor growth in ER-positive breast cancers, they also trigger a transcriptional program that favors immune evasion.

2019-07-27 | GSE134938 | GEO

Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells.

Project description:Among others, expression levels of programmed cell death 1 ligand 1 (PD-L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD-L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD-L1 downregulators. In addition, we identified that PD-L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ERα) inhibition triggers a broad immunosuppressive program in ER-positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen-presenting machinery. Accordingly, estrogen-deprived MCF7 cells are resistant to T-cell-mediated cell killing, in a manner that is independent of PD-L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER-positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion.

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Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells

Project description:Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells

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Nuclear Estrogen Receptor alpha (ERα) interactome following estrogen and antiestrogen treatment.

Project description:The Estrogen Receptor alpha (ERα) controls key cellular functions in hormone responsive breast cancer by assembling in large functional multiprotein complexes. ERα ligands are classified as agonists and antagonist, according to the response they elicit, thus the molecular characterization of the of ERα nuclear iteractome composition following estrogen and antiestrogen stimulation whose is needed to understand their effects on estrogen target tissues, in particular breast cancer. To this aim interaction proteomics coupled to mass spectrometry (MS) was applied to map the ERα nuclear interacting partners in MCF7 breast cancer cell nuclei following estrogen and antiestrogen stimuli.

2020-09-02 | PXD018709 | Pride

Estrogen deprivation triggers and immunosuppressive phenotype in breast cancer cells

Project description:Estrogen deprivation triggers and immunosuppressive phenotype in breast cancer cells

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BRCA1-mimetic compound NSC35446.HCl inhits IKKB expression by reducing estrogen receptor alpha occupancy in the IKKB promoter and inhibts NF-κB activity in anti-estrogen resitant human breast cells

Project description:We previously identified small molecules that fit into a BRCA1-binding pocket within estrogen receptor-alpha (ER), mimic the ability of BRCA1 to inhibit ER activity (“BRCA1-mimetics”), and overcome antiestrogen resistance. One such compound, the hydrochloride salt of NSC35446 (“NSC35446.HCl”), also inhibited growth of antiestrogen-resistant LCC9 tumor xenografts. The purpose of this study was to investigate the down-stream effects of NSC35446.HCl and its mechanism of action. Methods: Here, we studied antiestrogen-resistant (LCC9, T47DCO, MCF-7/RR, LY2), ER-negative (MDA-MB-231, HCC1806, MDA-MB-468), and antiestrogen-sensitive (MCF-7) cell lines. Techniques utilized include RNA-seq, qRT-PCR, cell growth analysis, cell-cycle analysis, Western blotting, luciferase reporter assays, TUNEL assays, in-silico analysis of the IKKB gene, and ChIP assays. Results: NSC35446.HCl inhibited proliferation and induced apoptosis in antiestrogen resistant LCC9, T47DCO, MCF-7/RR, and LY2 cells but not in ER-negative breast cancer cell lines. IKKB (IKKβ, IKBKB), an upstream activator of NF-B, was identified as a BRCA1-mimetic-regulated gene, based on an RNA-seq analysis; and NSC35446.HCl inhibited IKKB mRNA and protein expression in LCC9 cells. NSC35446.HCl also inhibited NF-B activity and expression of NF-B target genes. In-silico analysis of the IKKB promoter identified nine estrogen response element (ERE) half-sites and one ERE-like full-site. ChIP assays revealed that ER was recruited to the ERE-like full-site and five of the nine half-sites and that ER recruitment was inhibited by NSC35446.HCl in LCC9 and T47DCO cells. Conclusions: These studies identify functional EREs in the IKKB promoter and identify IKKB as an NSC35446.HCl-regulated gene; and they suggest that NF-B and IKKB, which were previously linked to antiestrogen resistance, are targets for NSC35446.HCl in reversing antiestrogen resistance.

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Project description:A hostile microenvironment in tumor tissues disrupts endoplasmic reticulum homeostasis and induces the unfolded protein response (UPR). A chronic UPR in both cancer cells and tumor-infiltrating leukocytes could facilitate evasion of immune surveillance. However, how the UPR in cancer cells cripples the anti-tumor immune response is unclear. Here, we demonstrate that, in cancer cells, the UPR component X-box binding protein 1 (XBP1) favors the synthesis and secretion of cholesterol, which activates myeloid-derived suppressor cells (MDSCs) and causes immunosuppression. Cholesterol is delivered in the form of small extracellular vesicle and internalized by MDSCs through macropinocytosis. Genetic or pharmacological depletion of XBP1 or reducing the tumor cholesterol content remarkably decreases MDSC abundance and triggers robust anti-tumor responses. Thus, our data unravel the cell non-autonomous role of XBP1/cholesterol signaling in the regulation of tumor growth and suggest its inhibition as a useful strategy for improving the efficacy of cancer immunotherapy.

2022-11-08 | GSE214662 | GEO

Glutamine deprivation triggers NAGK-dependent hexosamine salvage.

Project description:Tumors frequently exhibit aberrant glycosylation, which can impact cancer progression and therapeutic responses. The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. Prior studies have identified the HBP as a promising therapeutic target in pancreatic ductal adenocarcinoma (PDA). The HBP requires both glucose and glutamine for its initiation. The PDA tumor microenvironment is nutrient poor, however, prompting us to investigate how nutrient limitation impacts hexosamine synthesis. Here, we identify that glutamine limitation in PDA cells suppresses de novo hexosamine synthesis but results in increased free GlcNAc abundance. GlcNAc salvage via N-acetylglucosamine kinase (NAGK) is engaged to feed UDP-GlcNAc pools. NAGK expression is elevated in human PDA, and NAGK deletion from PDA cells impairs tumor growth in mice. Together, these data identify an important role for NAGK-dependent hexosamine salvage in supporting PDA tumor growth.

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