AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer

The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl+ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells. [Display omitted] •AXL + mammary epithelial cells have multipotent activity conserved in women and mice•AXL allows accesses to epithelial-to-mesenchymal transition genes and prevents differentiation into luminal cells•Deletion of Axl reduced incidence of Wnt1-driven tumors in mice•Provides a rationale explaining the advantage to cancer cells that co-opt AXL signaling Cell Biology; Stem Cells Research; Cancer