|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Kitajima, 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|
|Date Published||2017 Sep 07|
|Keywords||Animals, 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|
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.