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Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer.

ABSTRACT: Interleukin-6 (IL-6) is a pleiotropic cytokine with known multiple functions in immune regulation, inflammation, and oncogenesis. Binding of IL-6 to the IL-6 receptor (IL-6R) induces homodimerization and recruitment of glycoprotein 130 (gp130), which leads to activation of downstream signaling. Emerging evidence suggests that high levels of IL-6 are correlated with poor prognosis in breast cancer patients. IL-6 appears to play a critical role in the growth and metastasis of breast cancer cells, renewal of breast cancer stem cells (BCSCs), and drug resistance of BCSCs, making anti-IL-6/IL-6R/gp130 therapies promising options for the treatment and prevention of breast cancers. However, preclinical and clinical studies of the applications of anti-IL-6/IL-6R/gp130 therapy in breast cancers are limited. In this review, we summarize the structures, preclinical and clinical studies, mechanisms of action of chemical and biological blockers that directly bind to IL-6, IL-6R, or gp130, and the potential clinical applications of these pharmacological agents as breast cancer therapies.

SUBMITTER: Heo TH

PROVIDER: S-EPMC4941253 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer.

Heo Tae-Hwe TH Wahler Joseph J Suh Nanjoo N

Oncotarget 20160301 13

Interleukin-6 (IL-6) is a pleiotropic cytokine with known multiple functions in immune regulation, inflammation, and oncogenesis. Binding of IL-6 to the IL-6 receptor (IL-6R) induces homodimerization and recruitment of glycoprotein 130 (gp130), which leads to activation of downstream signaling. Emerging evidence suggests that high levels of IL-6 are correlated with poor prognosis in breast cancer patients. IL-6 appears to play a critical role in the growth and metastasis of breast cancer cells, ...[more]

PMID: 26840088

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Project description:Purpose: The hypoxic tumor microenvironment was reported to be involved in different tumorigenesis mechanisms of breast cancer (BC). We aimed to establish a hypoxia-related gene signature to identify a new BC subtype through the clustering analysis and explore potential compounds targeting the BC subtypes. Methods: Gene expression data and clinical features of BC and adjacent non-tumor tissues were downloaded from the Cancer Genome Atlas-Breast cancer (TCGA-BRCA) database. We comprehensively revealed the activity changes of Gene Ontology (GO) biological processes (BP) gene sets in BC by gene set variation analysis (GSVA) and identified three hypoxia-related BC subtypes. We then matched the differentially expressed gene profile of each subtype with the gene profile in CMap database to identify the potential agents targeting the BC subtypes. Results: 562 of Gene Ontology biological processes gene sets significantly correlated with hypoxia score in breast cancer. 969 BC patients were clustered into three subtypes based on the enrichment score of hypoxia-associated gene sets. Subtype 1 patients displayed better survival than subtype 2 and 3. KEGG pathway enrichment analysis of each subtype was performed based on the unique differential expression genes profile. In subtype 1, the upregulated genes were associated with lipid and amino acid metabolism regulation; in subtype 2, the upregulated genes were associated with metabolic energy regulation, while in subtype 3, the upregulated genes were associated with apoptosis and protein process. Using the CMap database, 55, 111 and 63 compounds were identified, targeting subtype 1, 2, and 3, respectively. Conclusion: In this study, novel hypoxia-related subtypes were developed for patients with BC. In addition, biological processes associated with differential expression genes profile and potential therapeutic target compounds were identified in each subtype. The new classification might provide a better understanding of the role of hypoxia in breast cancer and more individualized treatment for patients.

Dataset Information

Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer.

Publications

Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer.

Similar Datasets

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