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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 \u201cnoncanonical\u201d 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.<\/jats:p>","DOI":"10.1093\/narcan\/zcag016","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:52:34Z","timestamp":1785412354000},"source":"Crossref","is-referenced-by-count":0,"title":["Beyond the canonical view: steroid receptor network plasticity and mechanosensitive chromatin integration in breast cancer"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5771-0046","authenticated-orcid":false,"given":"Judith","family":"Garc\u00eda-Garc\u00eda","sequence":"first","affiliation":[{"name":"Department of Structural and Molecular Biology, Molecular Biology Institute of Barcelona (IBMB-CSIC) , E-8028, Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Sanz\u00a0P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Structural and Molecular Biology, Molecular Biology Institute of Barcelona (IBMB-CSIC) , E-8028, Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A Silvina","family":"Nacht","sequence":"additional","affiliation":[{"name":"Department of Structural and Molecular Biology, Molecular Biology Institute of Barcelona (IBMB-CSIC) , E-8028, Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4515-8058","authenticated-orcid":false,"given":"Diego M","family":"Presman","sequence":"additional","affiliation":[{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas - Universidad de Buenos Aires, Instituto de Fisiolog\u00eda, Biolog\u00eda Molecular y Neurociencias (IFIBYNE) , C1428, Buenos Aires ,","place":["Argentina"]},{"name":"Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Fisiolog\u00eda y Biolog\u00eda Molecular y Celular , C1428, Buenos Aires ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adali","family":"Pecci","sequence":"additional","affiliation":[{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas - Universidad de Buenos Aires, Instituto de Fisiolog\u00eda, Biolog\u00eda Molecular y Neurociencias (IFIBYNE) , C1428, Buenos Aires ,","place":["Argentina"]},{"name":"Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Qu\u00edmica Biol\u00f3gica, C1428 , Buenos Aires ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0554-2226","authenticated-orcid":false,"given":"Guillermo P","family":"Vicent","sequence":"additional","affiliation":[{"name":"Department of Structural and Molecular Biology, Molecular Biology Institute of Barcelona (IBMB-CSIC) , E-8028, Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"2026081202534574800_B1","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1210\/edrv-17-6-587","article-title":"Interaction of steroid hormone receptors with the transcription initiation complex","volume":"17","author":"Beato","year":"1996","journal-title":"Endocr Rev"},{"key":"2026081202534574800_B2","doi-asserted-by":"publisher","first-page":"3897","DOI":"10.1210\/en.2018-00831","article-title":"Deciphering steroid receptor crosstalk in hormone-driven cancers","volume":"159","author":"Truong","year":"2018","journal-title":"Endocrinology"},{"key":"2026081202534574800_B3","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.cell.2014.03.012","article-title":"Nuclear receptors, RXR, and the big bang","volume":"157","author":"Evans","year":"2014","journal-title":"Cell"},{"key":"2026081202534574800_B4","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1124\/pr.58.4.9","article-title":"International Union of Pharmacology. 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