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

Breast Cancer Res Treat. 2009 Nov;118(1):197-205. doi: 10.1007/s10549-008-0179-y. Epub 2008 Sep 12.

Abstract

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 alpha2beta1 integrin suppress breast tumor cell migration, we studied the impact of SEMA3A signaling on alpha2beta1 integrin expression/function. The incubation of breast tumor cells with SEMA3A increased alpha2 and beta1 integrin levels, and stimulated tumor cell adhesion to the alpha2beta1-binding matrix protein collagen I. Conversely, reducing SEMA3A expression in breast tumor cells decreased alpha2beta1 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 alpha2beta1-neutralizing antibody, we demonstrated that SEMA3A suppression of tumor cell migration is dependent on alpha2beta1. Our studies indicate that expression of the alpha2beta1 integrin, a suppressor of metastatic breast tumor growth, is stimulated in breast tumor cells by an autocrine SEMA3A pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Antibodies, Neutralizing / pharmacology
  • Autocrine Communication / physiology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Adhesion
  • Cell Line, Tumor / metabolism
  • Cell Line, Tumor / pathology
  • Cell Movement
  • Collagen Type I
  • Cytoskeleton / ultrastructure
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Integrin alpha2beta1 / antagonists & inhibitors
  • Integrin alpha2beta1 / biosynthesis
  • Integrin alpha2beta1 / genetics
  • Integrin alpha2beta1 / immunology
  • Integrin alpha2beta1 / physiology*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Neuropilin-1 / physiology
  • Recombinant Proteins / pharmacology
  • Semaphorin-3A / pharmacology
  • Semaphorin-3A / physiology*

Substances

  • Antibodies, Neutralizing
  • Collagen Type I
  • Integrin alpha2beta1
  • Neoplasm Proteins
  • Recombinant Proteins
  • SEMA3A protein, human
  • Semaphorin-3A
  • Neuropilin-1