Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis

Intratumoral hypoxia is a microenvironmental feature that promotes breast cancer progression and is asso-ciated with cancer mortality. Plexin B3 (PLXNB3) is highly expressed in estrogen receptor-negative breast cancer, but the underlying mechanisms and consequences have not been thoroughly investigated. Here, we report that PLXNB3 expression is increased in response to hypoxia and that PLXNB3 is a direct target gene of hypoxia-inducible factor 1 (HIF-1) in human breast cancer cells. PLXNB3 expression is correlated with HIF-1a immunohistochemistry, breast cancer grade and stage, and patient mortality. Mechanistically, PLXNB3 is required for hypoxia-induced MET/SRC/focal adhesion kinase (FAK) and MET/SRC/STAT3/ NANOG signaling as well as hypoxia-induced breast cancer cell migration, invasion, and cancer stem cell specification. PLXNB3 knockdown impairs tumor formation and lung metastasis in orthotopic breast cancer mouse models.

Automated summary

Intratumoral hypoxia promotes breast cancer progression and is associated with cancer mortality. This study reveals that Plexin B3 (PLXNB3) is highly expressed in estrogen receptor-negative breast cancer and is a direct target gene of hypoxia-inducible factor 1 (HIF-1). PLXNB3 is correlated with HIF-1a immunohistochemistry, breast cancer grade and stage, and patient mortality. Mechanistically, PLXNB3 is required for hypoxia-induced signaling and breast cancer cell migration, invasion, and cancer stem cell specification. Knockdown of PLXNB3 impairs tumor formation and lung metastasis in orthotopic breast cancer mouse models.