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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Retinoblastoma (RB) protein inactivation is linked to tumor progression, immature phenotypes, and therapy resistance.
• RB loss can drive undifferentiated phenotypes, as observed in a p53-null sarcoma model where interleukin-6 (IL-6) played a key role.

Purpose of the Study:

• To investigate the role of RB inactivation in breast cancer, focusing on its association with undifferentiated phenotypes and therapy resistance.
• To elucidate the mechanisms linking RB inactivation to IL-6 production, STAT3 activation, and metabolic reprogramming in breast cancer.

Main Methods:

• Gene Set Enrichment Analysis (GSEA) to identify RB inactivation signatures in breast cancer.
• Utilized RB-intact luminal-type (MCF-7) and RB-depleted basal-like breast cancer cell lines.
• Investigated the involvement of fatty acid oxidation (FAO), mitochondrial metabolism, c-Jun NH(2)-terminal kinase (JNK), and STAT3 signaling.

Main Results:

• Poorly differentiated breast cancers showed enrichment for an RB inactivation signature.
• RB inactivation in MCF-7 cells accelerated IL-6 secretion, creating an IL-6/STAT3 feed-forward loop that enhanced tumor growth and endocrine therapy resistance.
• RB inactivation-induced IL-6 production involved FAO-dependent mitochondrial metabolism and JNK signaling.
• IL-6, through STAT3, modulated mitochondrial superoxide levels to support stem cell-like activity.
• Low RB expression in luminal-type breast cancer patients correlated with genes involved in mitochondrial respiration and IL-6 targets.

Conclusions:

• RB protein suppresses malignant features by regulating metabolic reprogramming and cell-autonomous inflammation.
• RB inactivation promotes a pro-tumorigenic loop involving IL-6, STAT3, and altered mitochondrial function.
• Targeting metabolic pathways and IL-6 signaling may offer therapeutic strategies for RB-deficient cancers.