The Epigenetic Landscape of Promoter Genome-wide Analysis in Breast Cancer

Karslı-Çeppioğlu, Seher; Dagdemir, Aslihan; Judes, Gaëlle; Lebert, André; Penault‐Llorca, Frédérique; Bignon, Yves‐Jean; Bernard‐Gallon, Dominique

doi:10.1038/s41598-017-06790-z

Cited by 25 publications

(25 citation statements)

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“…Even though the precise signaling pathways behind the expression of these checkpoints are poorly understood, pre-clinical studies conducting with blockade of multiple checkpoints suggest that each of these molecules follows relatively unique pathways [ 27 , 28 ]. Recent advances in breast cancer research have emphasized that epigenetic modifications are correlated with cancer development and progression [ 5 , 29 , 30 ]. An improved understanding of these epigenetic regulations can pave the way to advance the concept of targeting immune checkpoints in cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Modifications in the epigenetic patterns of DNA are considered as an early event in the development of breast cancer [ 1 , 2 ]. Aberrant DNA methylation and repressive histone modifications are associated with clinical and histopathological features of breast cancer such as tumor subtype, stage, and differentiation [ 3 – 5 ]. In mammalian cells, the DNA can be modified by the methylation of cytosine residues in CpG dinucleotides and the N-terminal histone modifications through methylation, acetylation, phosphorylation, and ubiquitination [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer

et al. 2018

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BackgroundHigh expression of immune checkpoints in tumor microenvironment plays significant roles in inhibiting anti-tumor immunity, which is associated with poor prognosis and cancer progression. Major epigenetic modifications in both DNA and histone could be involved in upregulation of immune checkpoints in cancer.MethodsExpressions of different immune checkpoint genes and PD-L1 were assessed using qRT-PCR, and the underlying epigenetic modifications including CpG methylation and repressive histone abundance were determined using bisulfite sequencing, and histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) chromatin immunoprecipitation assays (ChIP), respectively.ResultsWe first assessed the expression level of six immune checkpoints/ligands and found that PD-1, CTLA-4, TIM-3, and LAG-3 were significantly upregulated in breast tumor tissues (TT), compared with breast normal tissues (NT). We investigated the epigenetic modifications beyond this upregulation in immune checkpoint genes. Interestingly, we found that CpG islands in the promoter regions of PD-1, CTLA-4, and TIM-3 were significantly hypomethylated in tumor compared with normal tissues. Additionally, CpG islands of PD-L1 promoter were completely demethylated (100%), LAG-3 were highly hypomethylated (80–90%), and TIGIT were poorly hypomethylated (20–30%), in both NT and TT. These demethylation findings are in accordance with the relative expression data that, out of all these genes, PD-L1 was highly expressed and completely demethylated and TIGIT was poorly expressed and hypermethylated in both NT and TT. Moreover, bindings of H3K9me3 and H3K27me3 were found to be reduced in the promoter loci of PD-1, CTLA-4, TIM-3, and LAG-3 in tumor tissues.ConclusionOur data demonstrate that both DNA and histone modifications are involved in upregulation of PD-1, CTLA-4, TIM-3, and LAG-3 in breast tumor tissue and these epigenetic modifications could be useful as diagnostic/prognostic biomarkers and/or therapeutic targets in breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0512-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer

et al. 2018

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“…In addition, promoter hypomethylation of three breast cancer stem cell-related genes (CD44, CD133, and MSH1), which strongly correlates with positive IHC staining and thus gene activation, has been shown to predict triple-negative status (103). Differences in histone modifications are also associated with differences in the expression of breast cancer genes across subtypes, separating luminal tumors, enriched with H3K27me3-modified genes, from nonluminal tumors (TNBC/HER2-positive), enriched with H3K9ac-regulated genes (104).…”

Section: Epigenetic Markers and Therapies In Tnbcmentioning

confidence: 99%

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

2019

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Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat. To date, therapies directed to specifi c molecular targets have rarely achieved clinically meaningful improvements in outcomes of patients with TNBC, and chemotherapy remains the standard of care. Here, we seek to review the most recent efforts to classify TNBC based on the comprehensive profi ling of tumors for cellular composition and molecular features. Technologic advances allow for tumor characterization at ever-increasing depth, generating data that, if integrated with clinical-pathologic features, may help improve risk stratifi cation of patients, guide treatment decisions and surveillance, and help identify new targets for drug development.Signifi cance: TNBC is characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival compared with other major breast cancer subtypes. The identifi cation of biomarkers that can help guide treatment decisions in TNBC remains a clinically unmet need. Understanding the mechanisms that drive resistance is key to the design of novel therapeutic strategies to help prevent the development of metastatic disease and, ultimately, to improve survival in this patient population. TNBC AND INTRINSIC BREAST CANCER SUBTYPESEarly transcriptomic profi ling of breast cancer using microarrays classifi ed tumors into fi ve intrinsic subtypes: luminal-A, luminal-B, HER2-enriched, basal-like, and a normal breast-like group ( 5,6 ). Although all intrinsic subtypes can be found within immunohistochemically defi ned triplenegative disease, basal-like tumors exhibit the greatest overlap with TNBC. Between 50% and 75% of TNBC have basal phenotype, and approximately 80% of basal-like tumors are ER-negative/HER2-negative ( Fig. 2 ; refs. 7, 8 ). Characterization Research.on August 1, 2020.

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“…Finally, in a cohort of 70 primary TNBC samples, novel methylation changes of specific genes in primary tumors and lymph node metastases were defined [ 71 ]. Distinct BC subtypes showed unique epigenetic patterns and marks [ 72 ]. The relationship between high levels of H3K9ac and better disease-free survival and metastatic-specific survival was reported [ 73 ].…”

Section: Epigenetics In Solid Cancersmentioning

confidence: 99%

Cancer epigenetics: Moving forward

et al. 2018

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Defects in chromatin modifiers and remodelers have been described both for hematological and solid malignancies, corroborating and strengthening the role of epigenetic aberrations in the etiology of cancer. Furthermore, epigenetic marks—DNA methylation, histone modifications, chromatin remodeling, and microRNA—can be considered potential markers of cancer development and progression. Here, we review whether altered epigenetic landscapes are merely a consequence of chromatin modifier/remodeler aberrations or a hallmark of cancer etiology. We critically evaluate current knowledge on causal epigenetic aberrations and examine to what extent the prioritization of (epi)genetic deregulations can be assessed in cancer as some type of genetic lesion characterizing solid cancer progression. We also discuss the multiple challenges in developing compounds targeting epigenetic enzymes (named epidrugs) for epigenetic-based therapies. The implementation of acquired knowledge of epigenetic biomarkers for patient stratification, together with the development of next-generation epidrugs and predictive models, will take our understanding and use of cancer epigenetics in diagnosis, prognosis, and treatment of cancer patients to a new level.

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The Epigenetic Landscape of Promoter Genome-wide Analysis in Breast Cancer

Cited by 25 publications

References 33 publications

DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer

DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

Cancer epigenetics: Moving forward

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