Investigation of the role for N-Acetylgalactosamine transferase 14 (GALNT14) in breast cancer metastasis to lungs

Abstract

Polypeptide N-acetyl-galactosaminyltransferases (GALNTs) have been shown to play diverse roles in several biological processes, but their function(s) in organ-tropic metastasis remains unknown. Here, we report that GALNT14 potentiates lung-specific metastasis of breast cancer by modulating two important steps during the metastatic process including initiation of metastatic colonies and their subsequent growth into overt metastases. Consistent with this, GALNT14 expression in primary breast tumors is specifically associated with pulmonary relapses in patients. Mechanistic studies suggest that GALNT14 augments metastasis initiation by attenuating bone morphogenetic protein (BMP) signaling in breast cancer cells, allowing them to self-renew against lung-derived BMPs. Furthermore, GALNT14 enables breast cancer cells not only to induce macrophage infiltration but also to exploit macrophage-derived fibroblast growth factors (FGFs) for their aggressive growth in the lung. Finally, we identified KRAS-PI3K-c-JUN signaling as an upstream pathway that accounts for elevated expression of GALNT14 in lung-metastatic breast cancer cells. Collectively, these findings uncovered an unprecedented role of GALNT14 in pulmonary metastasis of breast cancer and elucidated the underlying molecular mechanisms.