Oncogenic Ras-Src-cortactin signaling rewires actin-generated forces to drive basement membrane rupture and initiate breast cancer invasion

Oncogenic HRas activation plays a fundamental role in tumorigenesis, yet the cellular mechanisms by which HRas downstream signaling drives basement membrane (BM) disruption during early breast cancer invasion remain unclear. Using HRas-inducible breast spheroids, we demonstrate that HRas rewires cellular mechanotransduction of tumor-associated extracellular matrix stiffening to promote invasion. This process occurs independently of canonical myosin II-mediated contractility and proteolytic BM degradation. Transcriptomic and kinome profiling identified an HRas-Src-cortactin-Arp2/3 signaling axis that generates disruptive mechanical BM stress. We describe cortical triplet (CT) structures, defined by cortactin-dependent actin reinforcement and localized BM loss. CTs integrate increased cortical tension, actin polymerization forces, and myosin I-dependent contractility, thereby predicting invasion events. Pharmacological inhibition of Src or Arp2/3 reduced CT formation and invasion. Furthermore, elevated expression of HRas-cortactin-Arp2/3 axis components correlated with poor patient survival. Together, these findings uncover a previously unrecognized mechanism of early breast cancer invasion and highlight potential therapeutic targets.