Introduction

The evolution of breast cancer tumors toward metastasis involves the re-activation of
the developmental epithelial-to-mesenchymal (EMT) program that increases cell
migration and invasion5. TNBC cells display several such EMT features. The TAM
(TYRO3, AXL, MERTK) receptor tyrosine kinases (RTKs) form a distinct group that
is activated by the atypical vitamin K-dependent and γ-carboxylated ligands growth-
arrest-specific protein 6 (GAS6) and protein S (PROS) 6,7. TAMs exert their functions
in several biological processes, such as dampening the immune response and clearing
apoptotic cells8. Among TAMs, AXL expression is associated with metastasis in solid
cancers of several origins and correlates with poor patient survival 9. Despite its
overexpression in almost all TNBC cell lines, studies have shown AXL expression to
be subtype independent in patients’ breast tumors 10,11. AXL is not expressed in the
bulk of all breast tumors, but recent work suggests that its expression is in the cells
that acquire EMT features11. AXL is a particularly attractive therapeutic target in
metastatic cancers since it is involved in EMT and is positively correlated with
chemo-resistance and targeted drug resistance 12,13,14. AXL activation in epithelial
cancers is complex and can occur by crosstalk with other RTKs as well as ligand
binding. For example, AXL can be transactivated by HER2 and can function in a
GAS6-independent manner to promote metastasis 11. However, in marked contrast
with RTKs involved in cancer progression such as epidermal growth factor receptor
(EGFR) and mesenchymal-to-epithelial transition, little is known about the specific
mechanisms induced upon AXL activation to promote tumor invasiveness, metastasis,
and other features, such as drug resistance.