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 associated 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-1α 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. [Display omitted] •PLXNB3 expression is correlated with HIF signature and poor breast cancer prognosis•PLXNB3 is required for hypoxia-induced breast cancer cell migration and invasion•PLXNB3 is required for hypoxia-induced breast cancer stem cell enrichment•PLXNB3 regulates tumorigenesis and lung metastasis by activating MET signaling Zuo et al. show that HIF-1 stimulates PLXNB3 expression, which is required for breast cancer cell migration, invasion, and cancer stem cell specification. Hypoxia-induced PLXNB3 stimulates MET signaling to promote breast cancer tumorigenesis and lung metastasis.