MAGI1 inhibits the AMOTL2/p38 stress pathway and prevents luminal breast tumorigenesis

Alterations to cell polarization or to intercellular junctions are often associated with epithelial cancer progression, including breast cancers (BCa). We show here that the loss of the junctional scaffold protein MAGI1 is associated with bad prognosis in luminal BCa, and promotes tumorigenesis. E-cadherin and the actin binding scaffold AMOTL2 accumulate in MAGI1 deficient cells which are subjected to increased stiffness. These alterations are associated with IowYAP activity, the terminal Hippo-pathway effector, but with an elevated ROCK and p38 Stress Activated Protein Kinase activities. Blocking ROCK prevented p38 activation, suggesting that MAGI1 limits p38 activity in part through releasing actin strength. Importantly, the increased tumorigenicity of MAGI1 deficient cells is rescued in the absence of AMOTL2 or after inhibition of p38, demonstrating that MAGI1 acts as a tumor-suppressor in luminal BCa by inhibiting an AMOTL2/p38 stress pathway.

Automated summary

Loss of junctional scaffold protein MAGI1 is associated with poor prognosis in luminal breast cancer, promoting tumorigenesis through alterations in cell stiffness and signaling pathways. MAGI1 acts as a tumor suppressor in luminal breast cancer by inhibiting an AMOTL2/p38 stress pathway.