Abstract Mechanobiology investigates how cells sense and respond to physical cues such as stiffness, tension, and shear that shape cytoskeletal architecture, transcriptional programs, and cell behavior. In breast tumors, matrix stiffening and altered tensile forces strongly influence invasion and metastatic potential, and recent data show that invasive estrogen receptor (ER) positive tumors are unexpectedly stiffer and exhibit sharper stiffness gradients than ER-negative disease. Mechanical inputs remodel cytoskeletal and adhesion networks and activate signaling pathways that stabilize long-term behaviors, giving rise to mechanical memory. Although mechanical memory has been linked to durotaxis and poor outcomes, how estrogen intersects with stiffness to establish these structural states remains unclear. Here, we show that estrogen signaling directly enhances structural mechanical memory in breast cancer cells. Estrogen reorganizes focal adhesions and cortical actin architecture in a stiffness-dependent manner, increasing mechanosensing, traction generation, and durotactic migration on stiff substrates while stabilizing suppressive cortical actin bundles on soft substrates. These mechanically encoded states persist even after cells leave their original environment, and their magnitude correlates with estrogen receptor activity, aligning with emerging evidence that ER-positive tumors with strong stiffness-response signatures have worse clinical outcomes and show selective benefit from antifibrotic therapy. Together, these findings reveal that estrogen does not simply modulate gene expression but actively shapes the mechanical states that sustain invasion, identifying hormone-mechanics interactions as tractable targets for limiting progression in ER-positive breast cancer. Citation Format: Makena Manes, Samantha Hill, Robert Shaw, Yanqing Zhu, Marco Padilla-Rodriguez, Ghassan Mouneimne. Estrogen promotes structural memory in breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3479.
Manes et al. (Fri,) studied this question.