ESRRB: from embryonic development to cancer

Abstract ESRRB is an essential orphan nuclear receptor in embryonic development and in the maintenance of pluripotency. It can contribute to the self-renewal capacity of embryonic stem cells by regulating gene networks involved in cell fate decisions, influenced by core transcription factors such as NANOG, SOX2 and OCT4. Mechanistically, ESRRB links signaling inputs to chromatin accessibility and transcriptional output, enabling rapid switching between stable identity and lineage priming. Apart from its role in early development, growing evidence highlights ESRRB as a key regulator of cancer plasticity. The role of ESRRB in cancer appears to be context-dependent, as it can function either as a tumor promoter or suppressor, depending on the cancer type and cellular environment. In certain tumors, its expression has been linked to the maintenance of cancer stem cell-like properties, whereas in others, it has been associated with reduced proliferation and enhanced differentiation. Recent data further suggest that ESRRB splice isoforms (e.g., ESRRB2 and ESRRBΔ10) may encode distinct — sometimes opposing — functions that shape tumor behavior. Understanding ESRRB’s dual functions in development and tumorigenesis could provide valuable insights into mechanisms of plasticity and identify novel therapeutic targets for cancers with high adaptability.