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In this study, 2D and 3D in vitro breast cancer models were developed to investigate how ECM mechanics regulate cancer cell behavior. Hydrogel micropatterning enabled the mimicry of spatial confinement and stiffness in 2D microtumors, while drop\u2010on\u2010demand bioprinting facilitated the fabrication of mechanically tuneable 3D matrices. Phenotypic characterisation was conducted using immunofluorescence staining for molecular markers of plasticity and stemness, and drug resistance was assessed with doxorubicin and enzalutamide, the latter chosen for its emerging relevance in targeting stem\u2010like cancer cell populations. Soft matrices promoted stem\u2010like phenotypes, elevated ALDH1 expression, and enhanced drug resistance, whereas stiff matrices maintained a more differentiated profile. CD44 isoform expression was stiffness\u2010dependent, with the CD44 standard isoform enriched in soft matrices and the CD44 variant 9 isoform enriched in stiff matrices. The 3D matrices reproduced the mechanical regulation observed in 2D, providing a physiologically relevant platform for high\u2010throughput investigation of biomechanics\u2010driven cancer progression. These findings highlight the role of matrix stiffness in driving breast cancer phenotypic heterogeneity and support the application of microengineered synthetic matrices for studying metastasis and drug resistance.<\/jats:p>","DOI":"10.1002\/adhm.71371","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T11:29:11Z","timestamp":1782127751000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Matrix Stiffness Directs Stemness Signatures in Breast Cancer"],"prefix":"10.1002","volume":"15","author":[{"given":"Chantal","family":"Kopecky","sequence":"first","affiliation":[{"name":"School of Chemistry, Australian Centre for NanoMedicine, Faculty of Science UNSW Sydney  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3733-0890","authenticated-orcid":false,"given":"Elvis","family":"Pandzic","sequence":"additional","affiliation":[{"name":"Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre UNSW Sydney  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Porazinski","sequence":"additional","affiliation":[{"name":"Inventia Life Science  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Justin","family":"Gooding","sequence":"additional","affiliation":[{"name":"School of Chemistry, Australian Centre for NanoMedicine, Faculty of Science UNSW Sydney  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8963-9796","authenticated-orcid":false,"given":"Kristopher A","family":"Kilian","sequence":"additional","affiliation":[{"name":"School of Chemistry, Australian Centre for NanoMedicine, Faculty of Science UNSW Sydney  Sydney Australia"},{"name":"School of Materials Science &amp; 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