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The extracellular compartment plays a critical role in the intercellular communication during tumor initiation and progression. Although several mechanosensitive pathways have been described, the role of platelets (PLTs) in stiffness-driven signaling in the breast is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Extracellular soluble proteins were sampled in situ from live breast tissue using microdialysis. A total of 108 postmenopausal women were included: women with nondense or dense breasts, women with dense breasts randomized to low-dose acetylsalicylic acid (ASA; 160\u00a0mg\/day) or no treatment, and patients with estrogen receptor\u2013positive (ER\n                      <jats:sup>+<\/jats:sup>\n                      ) breast cancer. Breast density was assessed by magnetic resonance imaging. High-dimensional proteomic profiling of 1,158 proteins was performed using proximity extension assays. To investigate stiffness-dependent PLT responses, cells were cultured in a 3D in vitro system with tunable matrix stiffness generated by cross-linked hyaluronic acid, modeling nondense and dense breast tissue.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Dense breast tissue exhibited a distinct extracellular proteomic signature enriched for proteins associated with platelet activation, along with alterations in several immunomodulatory pathways. Several PLT-associated proteins were also elevated in ER\n                      <jats:sup>+<\/jats:sup>\n                      breast cancers, supporting their clinical relevance. Post hoc exploratory proteomic analysis of samples from women treated with low-dose ASA did not reveal modulation of these proteins, suggesting that stiffness-induced PLT activation may occur via mechanotransduction rather than biochemical pathways in vivo. Consistently, in the 3D in vitro model, increased matrix stiffness representative of dense breasts promoted a procoagulant PLT phenotype without corresponding changes in classical activation markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Tissue stiffness is a critical regulator of PLT mechanotransduction in dense breast tissue, contributing to a microenvironment permissive for cancer progression. These findings highlight PLT mechanobiology as a potential target for breast cancer prevention and therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:p>EudraCT: 2017-000317-22.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-026-03138-x","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T02:45:47Z","timestamp":1785984347000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Tissue-stiffness\u2013driven platelet activation emerges as a potential target for breast cancer prevention and treatment"],"prefix":"10.1186","volume":"24","author":[{"given":"Menikae K.","family":"Heenkenda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelie","family":"Abrahamsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Reustle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Aili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Lundberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas L.","family":"Lindahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7191-0018","authenticated-orcid":false,"given":"Charlotta","family":"Dabrosin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"issue":"6","key":"3138_CR1","first-page":"394","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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