Role of Semaphorin 3B (SEMA3B) in the Pathogenesis of Breast Cancer.

摘要

Semaphorin 3B is a secreted member of the semaphorin family, important in axonal guidance, which we and others have recently shown can act as a tumor suppressor by inducing apoptosis either by re-expression in tumor cells or applied as a soluble ligand. The common method of inactivation of SEMA3B is by allele loss and tumor acquired promoter methylation. Here we study the mechanism of SEMA3B effect on breast cancer cells. We found that vitamin D3 can induce SEMA3B protein and promoter activation. We find that VEGF(sub 165), which is reported to bind to neuropilin (NP), receptors for SEMA3B, significantly decreased the anti-mitotic effect of transfected or secreted SEMA3B on breast cancer cells. By contrast, VEGF(sub 121), a VEGF variant that lacks binding to NP-1 or NP-2 receptors, had no effect on SEMA3B growth suppressing activities. In addition, SEMA3B competed for binding of 125I- VEGF(SUB 165) to lung and breast cancer cells. In conclusion, we hypothesize that VEGF(sub 165), produced by tumor cells, acts as an autocrine survival factor and SEMA3B mediates its tumor suppressing effects, at least in part, by blocking this VEGF autocrine activity.