Semaphorin 3F inhibits breast cancer metastasis by regulating the Akt-mTOR and TGFβ signaling pathways via neuropilin-2.

Class 3 semaphorins are axon guidance factors implicated in tumor and vascular biology, including invasive activity. Recent studies indicate that semaphorin 3F (SEMA3F) is a potent inhibitor of metastasis; however, its functional role in breast cancer is not fully understood. We found that exogenous SEMA3F inhibited phosphorylation of Akt and mTOR downstream kinase S6K in MDA-MB-231 and MCF7 cells via neuropilin-2 (NRP2) receptor. We also examined the effect of SEMA3F on breast cancer progression in vivo allograft model. The mouse 4T1 breast cancer cells or 4T1 cells overexpressing SEMA3F (4T1-SEMA3F) were implanted into mammary fat pads of Balb/c mice. We found that tumor growth was significantly inhibited in 4T1-SEMA3F injected mice compared to controls. Immunostaining revealed a remarkable reduction in the expression of vimentin, a mesenchymal cell marker, in 4T1-SEMA3F tumors. We also observed that mice injected with 4T1-SEMA3F cells had minimal metastasis to the liver and lungs, compared to controls. As a novel feature, SEMA3F suppressed TGFβ-induced Smad2 phosphorylation, resulting in the inhibition of cell invasiveness and epithelial-to-mesenchymal transition (EMT) in breast cancer. Consistently, a significant correlation between reduced expression of SEMA3F and poor outcome in patients with breast cancer. We conclude that SEMA3F acts as a dual inhibitor of the Akt-mTOR and TGFβ signaling pathways; thus, it has the potential to treat metastatic breast cancer.