{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T19:03:55Z","timestamp":1791745435045,"version":"4.3.4"},"reference-count":177,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2023-00253408"],"award-info":[{"award-number":["RS-2023-00253408"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2023-00253408"],"award-info":[{"award-number":["RS-2023-00253408"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Drug resistance is a major cause of treatment failure in breast cancer, yet mutation-centered models do not fully explain delayed resistance, reversible tolerance, or re-sensitization after treatment interruption. Here, we synthesize recent findings in drug-tolerant persister (DTP) biology, clonal evolution, and tumor ecosystem dynamics to propose a breast cancer-focused Resistance Continuum as a conceptual framework for organizing the transition from initial therapy to stable resistance across ER-positive, HER2-positive, and triple-negative disease. Here, we synthesize recent findings in drug-tolerant persister (DTP) biology, clonal evolution, and tumor ecosystem dynamics to propose a breast cancer-focused Resistance Continuum as a conceptual framework for organizing the transition from initial therapy to stable resistance across ER-positive, HER2-positive, and triple-negative disease. This framework describes a canonical, but not universal, trajectory spanning treatment-na\u00efve heterogeneity, pre-adaptive priming, reversible DTP states, cycling persisters, and genetically stabilized resistant clones. We discuss how epigenetic and metabolic plasticity may sustain persistence, and we present epigenetic memory as an emerging hypothesis linking repeated non-genetic persistence to facilitated resistance in selected contexts. We also compare subtype-specific features of DTP biology, outline a multi-omics roadmap for interrogating the continuum, and highlight therapeutic opportunities for resistance interception. Overall, the Resistance Continuum is intended as a working scaffold to integrate current evidence and guide future mechanistic and translational studies.<\/jats:p>","DOI":"10.3390\/cells15090756","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T17:26:18Z","timestamp":1777051578000},"page":"756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pre-Adaptive States and Evolutionary Trajectories in Breast Cancer Drug Resistance: From Drug-Tolerant Persisters to Clonal Evolution"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3714-5700","authenticated-orcid":false,"given":"Hye Young","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Medicine, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"},{"name":"Department of Radiology, Gyeongsang National University Hospital, 79 Gangnam-ro, Jinju 52727, Republic of Korea"},{"name":"Institute of Medical Science, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1136-1763","authenticated-orcid":false,"given":"Mi Jung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Medicine, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"},{"name":"Department of Radiology, Gyeongsang National University Hospital, 79 Gangnam-ro, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Jun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Convergence Medical Sciences, Gyeongsang National University, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongyun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Convergence Medical Sciences, Gyeongsang National University, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-5213","authenticated-orcid":false,"given":"Ho-Cheol","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Radiology, Gyeongsang National University Hospital, 79 Gangnam-ro, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8571-2722","authenticated-orcid":false,"given":"Young-Sool","family":"Hah","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"},{"name":"Biomedical Research Institute, Gyeongsang National University Hospital, 79 Gangnam-ro, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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