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Multi-omics analysis of triple-negative breast cancers

ABSTRACT: Abstract The triple-negative breast cancer (TNBC) accounts for approximately 15% of all Breast Cancer (BC) cases. However, the prognosis and clinical outcomes of TNBC are worse than those of other BC subtypes due to a greater tumor and few therapeutically targetable oncogenic drivers. Numerous studies have employed genomic and transcriptomic approaches to identify clinically actionable TNBC subtypes in a comprehensive and unbiased manner using. While these analyses have advanced our knowledge of the molecular changes underlying TNBC, their clinical utility remains limited thus far. Given that proteins are the principal effector molecules of cellular signaling and function, we use a proteomic approach to quantitatively compare the abundances of 6,306 proteins across 55 formalin-fixed and paraffin-embedded (FFPE) TNBC tumors to reveal actionable pathways for anti-cancer treatment. We identified four major TNBC clusters by unsupervised clustering analysis of protein abundances. In addition, analyses of clinicopathological characteristics revealed associations between proteomic results and clinical phenotypes exhibited by each subtype. We validate the findings of our proteomics analysis, by inferring immune and stromal cell type composition from genome-wide DNA methylation profiles. Finally, quantitative proteomics on TNBC cell lines was conducted to identify representative in vitro models for each subtype. Collectively, our multi-omics data provide novel subtype-specific insights such as potential biomarkers, molecular drivers, and pharmacologic vulnerabilities for further investigations.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Arminja Kettenbach

PROVIDER: MSV000095715 | MassIVE | Wed Aug 28 17:33:00 BST 2024

SECONDARY ACCESSION(S): PXD055306

REPOSITORIES: MassIVE

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Project description:Triple negative breast cancer (TNBC) is a highly heterogeneous disease representing the most aggressive breast cancer (BC) subtype. Lack of Estrogen Receptor alpha (ERα), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu) expression makes TNBC immune to common therapies, significantly limiting the treatment options and suggesting the need to identify novel therapeutic targets. It was previously reported that Estrogen Receptor beta (ERβ) is expressed in a fraction of TNBC patients, where its presence correlates with improved patient outcome. Recently, we demonstrated an oncosuppressive ERβ effect in TNBC cell models expressing exogenous ERβ. On the other hand, it was shown that ERβ is involved in miRNA-mediated gene regulation in hormone-responsive BC cells, suggesting similar effect also in TNBC. To verify this hypothesis, we performed small non-coding RNA (sncRNA) sequencing on three engineered cell lines belonging to different TNBC molecular subtypes. ERβ-specific changes of sncRNA profile revealed that the major part of deregulated molecules are subtype specific, with only few commonly regulated ones. In order to validate the obtained results, we performed sncRNA profiling of 12 ERβ positive and 32 ERβ negative TNBC tissues, whose receptor status was assessed by immunohistochemistry in our previous research. Also here, ERβ-specific group of deregulated sncRNAs was identified. Interestingly, comparison of obtained in vitro and in vivo results revealed 2 differentially expressed miRNAs, displaying the same behavior in all three analyzed cell lines and tissues. In concordance with our previous results, IPA signaling pathway analysis performed on genes targeted by deregulated miRNAs highlighted downregulation of cholesterol biosynthesis pathway and upregulation of several signaling processes. Taken together, these findings suggest that ERβ is able to exert its oncosuppressive role in TNBC through miRNA-mediated regulation of gene expression.

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Multi-omics analysis of triple-negative breast cancers

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