{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:55:59Z","timestamp":1785394559074,"version":"3.55.0"},"reference-count":136,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Basic Sciences and the Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine"},{"name":"Hispanic Center of Excellence in Pharmacy, Loma Linda University Health School of Pharmacy"},{"name":"National Institutes of Health (NIH)\/National Institute of General Medical Sciences","award":["2R25GM060507"],"award-info":[{"award-number":["2R25GM060507"]}]},{"name":"Health Services Resources Administration","award":["DP34HP45725-01-00"],"award-info":[{"award-number":["DP34HP45725-01-00"]}]},{"name":"Union for International Cancer Control"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Breast cancer remains a leading cause of mortality among women worldwide. The inherent heterogeneity in tumors among patients with breast cancer poses a challenge to effective therapeutic management. The extracellular matrix (ECM) is an important structural component of the tumor microenvironment (TME) that regulates cellular behavior. When the ECM adopts a stiff configuration, this coincides with biochemical remodeling in response to biomechanical cues that drive tumor cell invasion, immune evasion, and metastatic spread in breast cancer. Emerging studies suggest that patient ancestry significantly impacts ECM stiffness to contribute to disparities in breast cancer survival. In this review, we discuss recent advances in our understanding of how the tumor ECM orchestrates breast cancer invasion and metastasis through mechanotransduction signaling to promote breast cancer progression. We also discuss ancestry-associated differences in breast ECM architecture and agents targeting mechanotransduction signaling pathways with potential to treat breast cancer and improve patient outcomes. Collectively, this review will highlight the significance of tumor mechanobiology and present emerging therapies that target stiffness-sensitive mechanotransduction pathways. By integrating mechanistic insights with therapeutic innovation, we aim to support the development of ECM-targeted therapies to enable more efficacious treatment of aggressive breast cancer subtypes.<\/jats:p>","DOI":"10.3390\/ijms27031510","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T16:46:28Z","timestamp":1770137188000},"page":"1510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting Matrix Stiffness and Mechanotransduction in Breast Cancer: Implications for Emerging Therapies"],"prefix":"10.3390","volume":"27","author":[{"given":"Michael","family":"Hall","sequence":"first","affiliation":[{"name":"Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA 92354, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozichi","family":"Amobi","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA 92354, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Khalaf","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA 92354, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9540-4117","authenticated-orcid":false,"given":"Afees John","family":"Olanrewaju","sequence":"additional","affiliation":[{"name":"Eureka Research Laboratory, Department of Anatomy, Babcock University, Ilishan-Remo 121103, Ogun State, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6535-3964","authenticated-orcid":false,"given":"Eileen","family":"Brantley","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA 92354, USA"},{"name":"Department of Pharmaceutical Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA 92354, USA"},{"name":"Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA 92354, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/s41586-020-03046-1","article-title":"Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis","volume":"589","author":"Pastushenko","year":"2021","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.cell.2004.06.006","article-title":"Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis","volume":"117","author":"Yang","year":"2004","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nallanthighal, S., Heiserman, J.P., and Cheon, D.J. 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