Tissue-stiffness–driven platelet activation emerges as a potential target for breast cancer prevention and treatment
Cell Communication and Signaling, 2026
Heenkenda M., Wang X., Zhong W., Abrahamsson A., Reustle N., Aili D., Lundberg P., Lindahl T., Dabrosin C.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology | Pathophysiology | Microdialysis Fluid |  Olink Target 96 |
Abstract
Background
High mammographic breast density is a strong independent risk factor for sporadic breast cancer, yet involved mechanisms remain poorly defined. 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.
Methods
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 mg/day) or no treatment, and patients with estrogen receptor–positive (ER + ) 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.
Results
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 + 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.
Conclusions
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.
Clinical trial registration
EudraCT: 2017-000317-22.