FIGURE 2.

Proposal of a tissue-level mechanism of warfarin’s putative anti-breast cancer effects. In mammary epithelia Axl signaling allow cells with progenitor properties access to stem-cell gene programs; engagement with the GAS6 ligand maintains progenitors in an undifferentiated state. Warfarin inhibits gamma-carboxylation of the Axl ligand, GAS6, preventing it from remaining anchored in the plasma membrane and essentially converting GAS6 from an agonist to an Axl-antagonist. At that point the progenitors may differentiate into more terminal states. Because the epithelial progenitors are thought to comprise breast cancer cells of origin, it might be more advantageous to force them to differentiate before they become a liability.