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Studies using transgenic mouse models of the mammary gland have revealed a cellular hierarchy in which both luminal and basal lineages are replenished by unipotent progenitor cells. Hence, despite the existence of bipotent stem cells, normal mammary gland homeostasis is intimately linked with unipotency. However, recent literature revealed that under specific physiological or experimental conditions, lineage-restricted mammary cells can reacquire multipotency and undergo a lineage switch, challenging the traditional unidirectional model of cell differentiation. This reactivation of multipotency has been observed<jats:italic>,<\/jats:italic> for instance, in response to pregnancy, lineage ablation or oncogenic stimuli<jats:italic>,<\/jats:italic> indicating a certain level of plasticity that may have consequences in the context of tumorigenesis. Understanding the molecular mechanisms governing this phenomenon could provide valuable insights into mammary gland cellular hierarchy and breast cancer progression. Indeed, reactivation of multipotency is a result of developed cell plasticity, which can drive tumor heterogeneity, promote disease aggressiveness and hamper diagnosis. This review provides an overview of models that have inferred reactivation of multipotency, discusses the underlying molecular and cellular mechanisms and proposes future perspectives for research.<\/jats:p>","DOI":"10.1007\/s10911-025-09586-4","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T17:41:45Z","timestamp":1752774105000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reactivation of Multipotency in the Mammary Gland \u2013 a Ripple in the Pond and a Turn of the Tide"],"prefix":"10.1007","volume":"30","author":[{"given":"C.","family":"Hager","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Jehanno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Bentires-Alj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"9586_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/171738a0","author":"MHF Wilkins","year":"1953","unstructured":"Wilkins MHF, Stokes AR, Wilson HR. 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