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Oncogene DOI:10.1038/onc.2017.124

The RB-IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity.

Publication TypeJournal Article
Year of Publication2017
AuthorsKitajima, S, Yoshida, A, Kohno, S, Li, F, Suzuki, S, Nagatani, N, Nishimoto, Y, Sasaki, N, Muranaka, H, Wan, Y, Thai, TC, Okahashi, N, Matsuda, F, Shimizu, H, Nishiuchi, T, Suzuki, Y, Tominaga, K, Gotoh, N, Suzuki, M, Ewen, ME, Barbie, DA, Hirose, O, Tanaka, T, Takahashi, C
JournalOncogene
Volume36
Issue36
Pages5145-5157
Date Published2017 Sep 07
ISSN1476-5594
KeywordsAnimals, Antineoplastic Agents, Hormonal, Apoptosis, Biomarkers, Tumor, Breast Neoplasms, Cell Differentiation, Cell Proliferation, Cell Self Renewal, Drug Resistance, Neoplasm, Fatty Acids, Female, Humans, Interleukin-6, Metabolome, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Retinoblastoma Protein, STAT3 Transcription Factor, Tamoxifen, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Abstract

Retinoblastoma (RB) protein inactivation during tumor progression is often associated with acquisition of immature phenotypes and resistance to therapy. Determination of an RB inactivation signature in a context of gaining undifferentiated phenotype in a p53-null sarcoma system revealed a critical role for interleukin (IL)-6. Using a Gene Set Enrichment Analysis (GSEA), we discovered that poorly differentiated breast cancers are enriched for this RB inactivation signature. Accelerated IL-6 secretion following RB inactivation in an RB-intact luminal-type breast cancer cell line MCF-7 promoted a positive feed forward loop between IL-6 and STAT3 driving tumor growth and endocrine therapy resistance. In addition, some of RB-intact basal-like type breast cancer cell lines exhibited a similar phenotype following RB depletion. The mechanism whereby RB inactivation increases IL-6 production in MCF-7 cells appeared to involve fatty acid oxidation (FAO)-dependent mitochondrial metabolism and c-Jun NH(2)-terminal kinase (JNK). In addition, IL-6, via STAT3-mediated feedback to mitochondria, autonomously adjusts mitochondrial superoxide to levels suitable to maintain stem cell-like activity. The gene expression profile of luminal-type breast cancer patients with low RB expression revealed high enrichment of genes involved in mitochondrial respiration and downstream targets of IL-6. These findings unveiled an unexpected strategy whereby RB suppresses malignant features of cancer cells through metabolic reprogramming and cell-autonomous inflammation.

DOI10.1038/onc.2017.124
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28481867?dopt=Abstract

Alternate JournalOncogene
PubMed ID28481867