Targeting Matrix Stiffness and Mechanotransduction in Breast Cancer: Implications for Emerging Therapies

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.