Beyond the canonical view: steroid receptor network plasticity and mechanosensitive chromatin integration in breast...

Steroid hormone receptors are traditionally described through models derived from simplified experimental conditions that do not fully recapitulate the physiological environment. In this review, we propose an integrated physiological framework for understanding steroid receptor function, in which chromatin organization, mechanotransduction, receptor network plasticity, and dynamic nuclear organization are recognized as fundamental components of hormone signaling rather than secondary regulatory layers. We highlight how steroid receptor signaling in breast cancer emerges from the coordinated integration of hormonal, chromatin, and mechanical cues, rather than from isolated ligand-driven events. In vivo, hormone responses occur within a complex endocrine milieu characterized by fluctuating hormone concentrations, multiple receptor interactions, and continuous communication with the chromatin landscape. Emerging evidence further indicates that biomolecular condensates and dynamic receptor assemblies contribute to the spatial and temporal coordination of transcriptional programs. By integrating advances in nuclear receptor biology, chromatin regulation, and mechanobiology, we argue that many mechanisms historically classified as "noncanonical" are more appropriately viewed as integral components of physiological steroid receptor function. This integrated perspective provides a broader framework for understanding breast cancer biology, disease progression, and therapeutic response.