Unknown,Transcriptomics,Genomics,Proteomics

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USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration

ABSTRACT: Breast cancer (BC), the most frequent tumor entity in women globally, shows a high therapeutic response in early and non-metastatic stages. However, triple-negative BC (TNBC), enriched with cancer stem cells (CSCs), presents significant challenges due to its chemoresistant and metastatic nature. Ubiquitin Specific Proteinase 22 (USP22) has emerged as a key player in promoting CSC functions, contributing to resistance to conventional therapies, tumor relapse, metastasis, and poor survival across various cancers, including BC. The specific role of USP22 in TNBC, however, remains underexplored. In this study, we employed the MMTV-cre, Usp22fl/fl transgenic mouse model to investigate USP22's influence on stem cell-like properties in mammary tissue. High-throughput transcriptomic analyses, combined with publicly available patient data and TNBC culture models, were utilized to elucidate USP22's role in CSC characteristics of TNBC. Our findings reveal that USP22 enhances CSC properties and drug tolerance by supporting oxidative phosphorylation, a key factor in the poor response to conventional therapies in aggressive BC subtypes. The study uncovers a novel tumor-supportive role of USP22 in sustaining cellular respiration, which contributes to the drug-tolerant behavior of HER2+-BC and TNBC cells. This highlights USP22 as a potential therapeutic target, offering new avenues to optimize standard treatments and address the aggressiveness of these malignancies.

INSTRUMENT(S): DNBSEQ-G400

ORGANISM(S): Homo sapiens

SUBMITTER: Florian Wegwitz

PROVIDER: E-MTAB-13577 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

Project description:BACKGROUND: Triple-negative breast cancer (TNBC) is insensitive to the most effective therapies for other breast cancers, including endocrine and Her2-directed therapies, thus the lack of specific treatments prompted us to search for new TNBC-associated molecules to be used as targets for cancer therapy. As patients with TNBC usually experience a quicker relapse and metastatic progression compared to other breast cancer subtypes, we hypothesized that cancer stem cells (CSC) could play a central role in TNBC. We thus directed our focus on genes differentially expressed between CSC and differentiated cancer cells of TNBC cell lines. RESULTS: We established tumorsphere cultures from mouse and human mammary cancer cell lines to enrich the CSC population. RNA-Seq was used to identify differences in gene expression between tumorspheres and their monolayer counterparts. Seventy-four transcripts were found up-regulated in the tumorspheres, while forty-two genes were down-regulated. Enrichment analysis of biological processes showed an up-regulation in genes involved in regulation of apoptosis in tumorspheres, and a down-regulation in genes involved in lipid metabolism and cell cycle regulation. By focusing on up-regulated genes coding for cell membrane-associated proteins, we selected Teneurin-4 (TENM4) as a candidate for further studies. Meta-analysis of publicly available datasets revealed that TENM4 mRNA is up-regulated in both lobular and ductal invasive carcinoma specimens compared to normal breast, and that high expression of TENM4 in TNBC patients shows a trend of correlation with a shorter relapse-free survival. 4T1 tumorspheres treated with a siRNA specific to TENM4 showed a decrease in TENM4 mRNA and protein levels, which was reflected by a significant impairment of tumorsphere-forming ability. TENM4 silencing also led to a decrease in Focal Adhesion Kinase (FAK) phosphorylation, which has been previously linked to CSC biology, thus strengthening the possible link between TENM4 and a CSC-like phenotype. CONCLUSIONS: Overall, our results indicate that the stem-like status of TNBC cells is accompanied by altered regulation of apoptosis, cell cycle and lipid metabolism pathways. Furthermore, we identified TENM4 as a potential novel player in CSC biology, and its potential role as a novel target to improve the outcome of TNBC patients in the future.

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USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration

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