Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

Magnani, Luca; Stoeck, Alexander; Zhang, Xiaoyang; Lánczky, András; Mirabella, Anne C.; Wang, Tian Li; Győrffy, Balázs; Lupien, Mathieu

doi:10.1073/pnas.1219992110

Cited by 152 publications

(142 citation statements)

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“…Epigenetic silencing of ER-responsive genes is conserved on the long term, and most probably involves negative regulators of proliferation. Epigenetic modifications and alterations of chromatin may contribute to ET resistance by altering ERa transcriptional activity and inducing a switch from classical ERa signaling to other signaling pathways through estrogen-responsive elements (34). In this process, several pioneer factors can dynamically modulate chromatin openness in breast cancer cells (35).…”

Section: Discussionmentioning

confidence: 99%

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

Cottu¹,

Bièche

Assayag³

et al. 2014

Clinical Cancer Research

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Purpose: Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC. Experimental Design: Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays. Results: HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival. Conclusions: PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314–25. ©2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

Cottu¹,

Bièche

Assayag³

et al. 2014

Clinical Cancer Research

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“…Genomic Region Enrichment was performed to find increased secretase activity which may account for an increased Notch signaling in endocrine resistant breast cancer cells (50). pF-03084014 which inhibits Notch signaling by reducing Notch intracellular domain (NICD) and Notch target genes Hes-1 and c-Myc in both cells and tumors prominently enhanced the antitumor activity of docetaxel in MDA-Mb-231 xenograft model through suppressing expression of survivin and myeloid cell leukemia sequence 1 (MCL1), reducing ABCB1 and ABCC2, upregulating BIM and reversing the EMT phenotype (51).…”

Section: Emt-related Signal Pathways and Drug Resistance In Breast Camentioning

confidence: 99%

Epithelial-mesenchymal transition and drug resistance in breast cancer (Review)

Huang

Ren

2015

International Journal of Oncology

126

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Abstract. Breast cancer is the leading cause of cancer death in women worldwide. Insensitivity of tumor cells to drug therapies is an essential reason arousing such high mortality. Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. It is well known that EMT plays an important role in breast cancer progression. Recently, mounting evidence has demonstrated involvement of EMT in antagonizing chemotherapy in breast cancer. Here, we discuss the biological significance and clinical implications of these findings, with an emphasis on novel approaches that effectively target EMT to increase the efficacy of anticancer therapies.

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“…We postulated that the lack of repressive histone modifications would affect chromatin accessibility and subsequent activation of the lineage-specifying loci. To directly test this, we employed a genome-wide sequencing technique (formaldehydeassisted isolation of regulatory elements [FAIRE-Seq]) that measures chromatin accessibility by depleting nucleosome-rich areas of DNA (52,53). Following examination of the Foxp3 locus in naive G9a fl/fl Th cells, we found much fewer nucleosome-free accessible sites ( Figure 9C).…”

Section: G9a-deficient T Cells Display Increased Sensitivity To Tgf-β1mentioning

confidence: 99%

Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation

et al. 2014

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Inflammatory bowel disease (IBD) pathogenesis is associated with dysregulated CD4 + Th cell responses, with intestinal homeostasis depending on the balance between IL-17-producing Th17 and Foxp3 + Tregs. Differentiation of naive T cells into Th17 and Treg subsets is associated with specific gene expression profiles; however, the contribution of epigenetic mechanisms to controlling Th17 and Treg differentiation remains unclear. Using a murine T cell transfer model of colitis, we found that T cell-intrinsic expression of the histone lysine methyltransferase G9A was required for development of pathogenic T cells and intestinal inflammation. G9A-mediated dimethylation of histone H3 lysine 9 (H3K9me2) restricted Th17 and Treg differentiation in vitro and in vivo. H3K9me2 was found at high levels in naive Th cells and was lost following Th cell activation. Loss of G9A in naive T cells was associated with increased chromatin accessibility and heightened sensitivity to TGF-β1. Pharmacological inhibition of G9A methyltransferase activity in WT T cells promoted Th17 and Treg differentiation. Our data indicate that G9A-dependent H3K9me2 is a homeostatic epigenetic checkpoint that regulates Th17 and Treg responses by limiting chromatin accessibility and TGF-β1 responsiveness, suggesting G9A as a therapeutic target for treating intestinal inflammation. IntroductionThe inflammatory bowel diseases (IBDs) are a group of chronic intestinal inflammatory diseases that include ulcerative colitis (UC) and Crohn disease (CD). IBD is thought to occur as a result of a complex interplay between host genetics and environmental factors leading to a dysregulated intestinal immune response (1). A recent meta-analysis of existing genome-wide association studies identified over 160 loci associated with both UC and CD (2). Gene ontology (GO) analysis of these IBD loci showed that the terms "regulation of cytokine production" and "T cell activation" were significantly enriched (2), suggesting that dysregulated production of cytokines by activated T cells is a critical factor in the development of IBD. Thus, a better understanding of the molecular mechanisms that regulate T cell activation and function may provide novel pathways to target therapeutically.A pathogenic role for CD4 + Th cells in intestinal inflammation has been clearly shown in a murine T cell transfer model of IBD. Adoptive transfer of highly purified naive CD4 + CD25 -CD45RB hi Th cells into immunodeficient Rag1 -/-mice results in the development of chronic intestinal inflammation, leading to weight loss and death (3,4). Disease pathology of Th cell transfer colitis shares many similarities with human IBD, including transmural inflammation,

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Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

Cited by 152 publications

References 99 publications

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

Epithelial-mesenchymal transition and drug resistance in breast cancer (Review)

Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation

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