Autocrine semaphorin3A stimulates alpha2 beta1 integrin expression/function in breast tumor cells

The axon repulsion factor semaphorin3A (SEMA3A) and its receptor neuropilin-1 (NP-1) are expressed in breast tumor cells, and function as suppressors of tumor cell migration. Based on the knowledge that both SEMA3A and the alpha 2 beta 1 integrin suppress breast tumor cell migration, we studied the impact of SEMA3A signaling on alpha 2 beta 1 integrin expression/function. The incubation of breast tumor cells with SEMA3A increased alpha 2 and beta 1 integrin levels, and stimulated tumor cell adhesion to the alpha 2 beta 1-binding matrix protein collagen I. Conversely, reducing SEMA3A expression in breast tumor cells decreased alpha 2 beta 1 levels and collagen adhesion. The ability of SEMA3A to increase tumor cell adhesion to collagen was dependent on both the SEMA3A receptor NP-1 and the glycogen synthase kinase-3. The incubation of breast tumor cells with SEMA3A disrupted the actin cytoskeleton, and reduced both tumor cell migratory and invasive behavior. Importantly, using an alpha 2 beta 1-neutralizing antibody, we demonstrated that SEMA3A suppression of tumor cell migration is dependent on alpha 2 beta 1. Our studies indicate that expression of the alpha 2 beta 1 integrin, a suppressor of metastatic breast tumor growth, is stimulated in breast tumor cells by an autocrine SEMA3A pathway.