Longevity & AgingDual FOXA1 Mutations Drive Prostate Cancer or Therapy Resistance via Opposite Mechanisms
FOXA1 is mutated in 10–40% of prostate cancers globally, yet its in vivo oncogenic roles were poorly understood. Researchers at the University of Michigan generated knock-in mouse models carrying distinct human FOXA1 mutation classes. Class 1 mutations, combined with p53 loss, drove AR-positive invasive adenocarcinomas through co-activation of mTORC1/2 and oncogenic AR signaling via chimeric AR-half enhancers. Class 2 mutations, by contrast, reprogrammed differentiated luminal cells into a progenitor-like state by activating KLF5 and AP-1 neo-enhancer circuits, enabling tumor cell survival under castrate androgen levels. These findings establish FOXA1 as a multifaceted oncogene whose distinct mutational classes divergently evolve—one driving tumor initiation, the other enabling therapy-resistant progression.
