Podoplanin regulates mammary stem cell function and tumorigenesis by potentiating Wnt/β-catenin signaling

Abstract

Stem cells (SC) drive mammary development, giving rise postnatally to an epithelial bilayer composed of luminal and basal myoepithelial cells. Deregulation of SCs is thought to be at the origin of certain breast cancers, however the molecular identity of SCs and the factors regulating their function remain poorly defined. We identified the transmembrane protein, Podoplanin (Pdpn), as a specific marker of the basal compartment, including multipotent SCs, and found Pdpn localized at the basal-luminal interface. Embryonic deletion of Pdpn targeted to basal cells diminished basal and luminal SC activity and affected expression of several Wnt/β-catenin (Wnt/β-cat) signaling components in basal cells. Moreover, Pdpn loss attenuated mammary tumor formation in a mouse model of β-cat-induced breast cancer, limiting tumor-initiating cell expansion and promoting molecular features associated with mesenchymal-to-epithelial cell transition. In line with the loss-of-function data, we demonstrated that mechanistically, Pdpn enhanced Wnt/β-cat signaling in mammary basal cells. Overall, this study uncovers a role for Pdpn in mammary SC function and importantly, identifies Pdpn as a new regulator of Wnt/β-cat signaling, a key pathway in mammary development and tumorigenesis.