Defining super-enhancer landscape in triple-negative breast cancer by multiomic profiling.
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ABSTRACT:
SUBMITTER: Huang H
PROVIDER: S-EPMC8046763 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Here we apply integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes, and provide clinically relevant biological insights towards TNBC. Using CRISPR/Cas9-mediated gene editing, we identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1 and MET, thereby unveiling a mechanism for specific overexpression of the key oncogenes in TNBC. We also identify ANLN as a novel TNBC-specific gene regulated by super-enhancer. Our studies reveal a TNBC-specific epigenomic landscape, contributing to the dysregulated oncogene expression in breast tumorigenesis.
2021-03-04 | PXD024505 | iProX
Project description:Triple Negative Breast Cancer (TNBC) is a heterogeneous disease lacking known molecular drivers and effective targeted therapies. Cytotoxic chemotherapy remains the mainstay of treatment for TNBCs, which have significantly poorer survival rates compared to other breast cancer subtypes. In addition to changes within the coding genome, aberrant enhancer activity is a well-established contributor to tumorigenesis. Here we use H3K27Ac chromatin immunoprecipitation followed by sequencing (ChIP-Seq) to map the active cis-regulatory landscape in TNBC. We identify distinct disease subtypes associated with specific enhancer activity, and over 2,500 unique superenhancers acquired by tumor cells but absent from normal breast tissue. To identify potential actionable disease drivers, we probed the dependency on genes that associate with tumor-specific enhancers by CRISPR screening. In this way we identify a number of tumor-specific dependencies, including a previously uncharacterized dependency on the TGFβ pseudo-receptor BAMBI.
| S-EPMC7316302 | biostudies-literature
Project description:BackgroundRecent efforts of genome-wide gene expression profiling analyses have improved our understanding of the biological complexity and diversity of triple-negative breast cancers (TNBCs) reporting, at least six different molecular subtypes of TNBC namely Basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR). However, little is known regarding the potential driving molecular events within each subtype, their difference in survival and response to therapy. Further insight into the underlying genomic alterations is therefore needed.Patients and methodsThis study was carried out using copy-number aberrations, somatic mutations and gene expression data derived from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas. TNBC samples (n?=?550) were classified according to Lehmann's molecular subtypes using the TNBCtype online subtyping tool (http://cbc.mc.vanderbilt.edu/tnbc/).ResultsEach subtype showed significant clinic-pathological characteristic differences. Using a multivariate model, IM subtype showed to be associated with a better prognosis (HR?=?0.68; CI?=?0.46-0.99; P?=?0.043) whereas LAR subtype was associated with a worst prognosis (HR?=?1.47; CI?=?1.0-2.14; P?=?0.046). BL1 subtype was found to be most genomically instable subtype with high TP53 mutation (92%) and copy-number deletion in genes involved in DNA repair mechanism (BRCA2, MDM2, PTEN, RB1 and TP53). LAR tumours were associated with higher mutational burden with significantly enriched mutations in PI3KCA (55%), AKT1 (13%) and CDH1 (13%) genes. M and MSL subtypes were associated with higher signature score for angiogenesis. Finally, IM showed high expression levels of immune signatures and check-point inhibitor genes such as PD1, PDL1 and CTLA4.ConclusionOur findings highlight for the first time the substantial genomic heterogeneity that characterize TNBC molecular subtypes, allowing for a better understanding of the disease biology as well as the identification of several candidate targets paving novel approaches for the development of anticancer therapeutics for TNBC.
| S-EPMC5913636 | biostudies-literature
Project description:Triple-negative breast cancer is a heterogeneous disease characterized by poor clinical outcomes and a shortage of targeted treatment options. To discover molecular features of triple-negative breast cancer, we performed quantitative proteomics analysis of twenty human-derived breast cell lines and four primary breast tumors to a depth of more than 12,000 distinct proteins. We used this data to identify breast cancer subtypes at the protein level and demonstrate the precise quantification of biomarkers, signaling proteins, and biological pathways by mass spectrometry. We integrated proteomics data with exome sequence resources to identify genomic aberrations that affect protein expression. We performed a high-throughput drug screen to identify protein markers of drug sensitivity and understand the mechanisms of drug resistance. The genome and proteome provide complementary information that, when combined, yield a powerful engine for therapeutic discovery. This resource is available to the cancer research community to catalyze further analysis and investigation.
| S-EPMC4425736 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Genomic sequencing has detected a distinctive mutational portrait of both the germline and somatic alterations in TNBC, which is staggeringly different from other breast cancer subtypes. The clinical utility of sequencing germline BRCA1/2 genes has been well established in TNBC. However, for other predisposition genes, studies concerning the risk and penetrance to TNBC are relatively scarce. Very few recurrent mutations, including TP53 and PI3KCA mutations, together with a long tail of individually rare mutations occur in TNBC. These combined effects of genomic alterations drive TNBC progression. Given the complexity and heterogeneity of TNBC, clinical interpretation of the genomic alterations in TNBC may pave a new way for the treatment of TNBC. In this review, we summarized the germline and somatic mutation profiles of TNBC and discussed the current and upcoming therapeutic strategies targeting the mutant proteins or pathways to enable tailored-therapeutics.
| S-EPMC6046102 | biostudies-literature
Project description:The human HCC1806 cell line is frequently used as a preclinical model for triple negative breast cancer (TNBC). Given that dysregulated epigenetic mechanisms are involved in cancer pathogenesis, emerging therapeutic strategies target chromatin regulators, such as histone deacetylases. A comprehensive understanding of the epigenome and transcription profiling in HCC1806 provides the framework for evaluating efficacy and molecular mechanisms of epigenetic therapies. Thus, to study the interplay of transcription and chromatin in the HCC1806 preclinical model, we performed nascent transcription profiling using Precision Run-On coupled to sequencing (PRO-seq). Additionally, we mapped the genome-wide locations for RNA polymerase II (Pol II), the histone variant H2A.Z, seven histone modifications, and CTCF using ChIP-exo. ChIP-exonuclease (ChIP-exo) is a refined version of ChIP-seq with near base pair precision mapping of protein-DNA interactions. In this Data Descriptor, we present detailed information on experimental design, data generation, quality control analysis, and data validation. We discuss how these data lay the foundation for future analysis to understand the relationship between the nascent transcription and chromatin.
| S-EPMC6400101 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is known to have a poor prognosis and limited treatment options, namely chemotherapy. Different molecular studies have recently classified TNBC into different subtypes opening the door to potential new-targeted treatment options. In this review, we discuss the current standard of care in the treatment of TNBC in the neoadjuvant, adjuvant and metastatic settings. In addition, we summarize the ongoing phase III clinical trials evaluating different associations between the 3 pillars of anticancer treatment: chemotherapy, targeted therapy and immunotherapy.
| S-EPMC6682754 | biostudies-literature
Project description:Background: To classify triple-negative breast cancer (TNBC) immunotyping using the public database, analyze the differences between subtypes in terms of clinical characteristics and explore the role and clinical significance of immune subtypes in TNBC immunotherapy. Methods: We downloaded TNBC data from the cBioPortal and GEO databases. The immune genes were grouped to obtain immune gene modules and annotate their biological functions. Log-rank tests and Cox regression were used to evaluate the prognosis of immune subtypes (IS). Drug sensitivity analysis was also performed for the differences among immune subtypes in immunotherapy and chemotherapy. In addition, dimension reduction analysis based on graph learning was utilized to reveal the internal structure of the immune system and visualize the distribution of patients. Results: Significant differences in prognosis were observed between subtypes (IS1, IS2, and IS3), with the best in IS3 and the worst in IS1. The sensitivity of IS3 to immunotherapy and chemotherapy was better than the other two subtypes. In addition, Immune landscape analysis found the intra-class heterogeneity of immune subtypes and further classified IS3 subtypes (IS3A and IS3B). Immune-related genes were divided into seven functional modules (The turquoise module has the worst prognosis). Five hub genes (RASSF5, CD8A, ICOS, IRF8, and CD247) were screened out as the final characteristic genes related to poor prognosis by low expression. Conclusions: The immune subtypes of TNBC were significantly different in prognosis, gene mutation, immune infiltration, drug sensitivity, and heterogeneity. We validated the independent role of immune subtypes in tumor progression and immunotherapy for TNBC. This study provides a new perspective for personalized immunotherapy and the prognosis evaluation of TNBC patients in the future.
| S-EPMC8593253 | biostudies-literature
Project description:Triple-negative breast cancer is a heterogeneous disease characterized by poor clinical outcomes and a shortage of targeted treatment options. To discover molecular features of triple-negative breast cancer, we performed quantitative proteomics analysis of twenty human-derived breast cell lines and four primary breast tumors to a depth of more than 12,000 distinct proteins. We used this data to identify breast cancer subtypes at the protein level and demonstrate the precise quantification of biomarkers, signaling proteins, and biological pathways by mass spectrometry. We integrated proteomics data with exome sequence resources to identify genomic aberrations that affect protein expression. We performed a high-throughput drug screen to identify protein markers of drug sensitivity and understand the mechanisms of drug resistance. The genome and proteome provide complementary information that, when combined, yield a powerful engine for therapeutic discovery. This resource is available to the cancer research community to catalyze further analysis and investigation.
2017-12-12 | PXD008222 | Pride
Project description:BackgroundBreast cancer development and progression involve both germline and somatic mutations. High-throughput genotyping and next-generation sequencing technologies have enabled discovery of genetic risk variants and acquired somatic mutations driving the disease. However, the possible oncogenic interactions between germline genetic risk variants and somatic mutations in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) have not been characterized. Here, we delineated the possible oncogenic interactions between genes containing germline and somatic mutations in TNBC and non-TNBC and investigated whether there are differences in gene expression and mutation burden between the two types of breast cancer.MethodsWe addressed this problem by integrating germline mutation information from genome-wide association studies with somatic mutation information from next-generation sequencing using gene expression data as the intermediated phenotype. We performed network and pathway analyses to discover molecular networks and signalling pathways enriched for germline and somatic mutations.ResultsThe investigation revealed signatures of differentially expressed and differentially somatic mutated genes between TNBC and non-TNBC. Network and pathway analyses revealed functionally related genes interacting in gene regulatory networks and multiple signalling pathways enriched for germline and somatic mutations for each type of breast cancer. Among the signalling pathways discovered included the DNA repair and Androgen and ATM signalling pathways for TNBC and the DNA damage response, molecular mechanisms of cancer, and ATM and GP6 signalling pathways for non-TNBC.ConclusionsThe results show that integrative genomics is a powerful approach for delineating oncogenic interactions between genes containing germline and genes containing somatic mutations in TNBC and non-TNBC and establishes putative functional bridges between genetic and somatic alterations and the pathways they control in the two types of breast cancer.
| S-EPMC7364202 | biostudies-literature