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Although its loss of expression has been linked to breast cancer invasion and metastasis, the underlying mechanisms driving tumour progression upon mutational Afadin (<jats:italic>AFDN<\/jats:italic>) loss in breast cancers remains unclear. In the current study we identified a somatic frameshift <jats:italic>AFDN<\/jats:italic> mutation (<jats:italic>p<\/jats:italic>.Lys630fs) in an invasive breast cancer sample that coincides with loss of Afadin protein expression. Functional studies in E\u2010cadherin\u2010expressing breast cancer cells show that Afadin loss leads to immature and aberrant adherens junction (AJ) formation. The lack of AJ maturation results in a noncohesive cellular phenotype accompanied by Actomyosin\u2010dependent anoikis resistance, which are classical progression hallmarks of single\u2010cell breast cancer invasion. Reconstitution experiments using Afadin truncates show that proper F\u2010actin organisation and epithelial cell\u2013cell adhesion critically depend on the Coiled\u2010Coil domain of Afadin but not on the designated C\u2010terminal F\u2010actin binding domain. Mouse xenograft experiments based on cell lines and primary patient\u2010derived breast cancer organoids demonstrate that Afadin loss induces single\u2010cell lobular\u2010type invasion phenotypes and overt dissemination to the lungs and the peritoneum. In short, Afadin is a metastasis suppressor for breast cancer through stabilisation and maturation of a mechanical E\u2010cadherin to F\u2010actin outside\u2010in link. \u00a9 2025 The Author(s). <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6394","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T05:15:33Z","timestamp":1741756533000},"page":"26-39","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Afadin loss induces breast cancer metastasis through destabilisation of E\u2010cadherin to F\u2010actin linkage"],"prefix":"10.1002","volume":"266","author":[{"given":"Max AK","family":"R\u00e4tze","sequence":"first","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  Utrecht The 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