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Type II interleukin-4 receptor activation promotes tumor pro-gression in basal breast cancer cells via metabolic and epige-netic modulation

ABSTRACT: Interleukin-4 (IL4) is a Th2 cytokine that can signal through two different receptors, one of which – the type II receptor - is overexpressed by various cancer cells. Previously we have shown that type II IL4 receptor signaling increases proliferation and metastasis in mouse models of breast cancer, as well as increasing glucose and glutamine metabolism. Here we expand on those findings to determine mechanistically how IL4 signaling links glucose metabolism and histone acetylation to drive proliferation in the context of triple-negative breast cancer (TNBC). We used a combination of cellular, biochemical and genomics approaches to interrogate TNBC cell lines, which represent a cancer type where high expression of the type II IL4 receptor is linked with reduced survival. Our results indicate that type II IL4 receptor activation leads to increased glucose uptake, Akt and ACLY activation,and histone acetylation in TNBC cell lines. Inhibition of glucose uptake through deletion of Glut1 ablates IL4-induced proliferation. Additionally, pharmacological inhibition of histone acetyltransferase P300 attenuates IL4-mediated gene expression, and proliferationin vitro. Our work elucidates a role for type II IL4 receptor signaling in promoting TNBC progression, and highlights type II IL4 signaling as well as histone acetylation as possible targets for therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264721 | GEO | 2025/04/23

REPOSITORIES: GEO

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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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Type II interleukin-4 receptor activation promotes tumor pro-gression in basal breast cancer cells via metabolic and epige-netic modulation

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