Tumor suppressor FRMD3 Controls Mammary Epithelial Cells Fate Decision via Notch signaling pathway

Luminal to basal transition in mammary gland is accompanied by the changes of epithelial cell lineage plasticity, however, the underlying mechanism remains elusive. Here, we demonstrated that loss of the scaffold protein FRMD3 in breast cancer predicts poor outcomes. Knockout of Frmd3 inhibits mammary gland lineage development and induces mammary epithelium cells (MECs) stemness, and later on emerge of TNBC. Loss of Frmd3 in PyMT mice results in luminal to basal phenotype transition. Single- MEC mRNA sequencing analysis indicated that knockout of Frmd3 corresponds to inhibition of Notch signaling pathway. Mechanistically, FRMD3 assists Dishevelled-2 degradation via enhancing its interaction with the deubiquitinase USP9x. FRMD3 also interrupts the interaction of Dishevelled-2 with CK1, FOXK1, FOXK2 and NICD, causing a decrease in Dishevelled-2 phosphorylation, entry into the nucleus and impairing the Notch-dependent luminal epithelial lineage plasticity in MECs respectively. Taken together, FRMD3 is a tumor suppressor and an endogenous activator of the Notch signaling pathway that regulates mammary epithelial cell lineage plasticity.