Osteopontin (OPN) is a secreted
phosphoprotein that has been associated with
malignancy of breast and other
cancers. OPN binds to several cell surface
integrins including alpha(v)beta(3), alpha(v)beta(5), and alpha(v)beta(1). Although the relative contribution of these
integrins to
breast cancer cell
malignancy is uncertain, correlative studies suggest that alpha(v)beta(3) may be particularly associated with increased
tumor aggressiveness. Previously, we reported that tumorigenic, nonmetastatic 21NT mammary
carcinoma cells respond to OPN through alpha(v)beta(5) and alpha(v)beta(1) but not alpha(v)beta(3). Here, we determined that 21NT cells lack beta(3) expression, and we asked whether expression of alpha(v)beta(3) could enhance the ability of
breast cancer cells to respond to the
malignancy-promoting effects of OPN both in vitro and in vivo. 21NT cells stably transfected with beta(3) showed significantly increased adhesion, migration, and invasion to OPN in vitro compared with vector control. To determine if beta(3) could also enhance the response of breast epithelial cells to OPN in vivo, cells stably transfected with both beta(3) and OPN (NT/Obeta(3)) were injected into the mammary fat pad of female nude mice and primary
tumor growth was assessed relative to controls. Mice injected with NT/Obeta(3) cells demonstrated a significantly increased primary
tumor take (75% of mice) compared with controls (0-12.5% of mice) as well as a decreased
tumor doubling time and a decreased
tumor latency period. These results suggest that increased expression of the alpha(v)
beta(3) integrin during
breast cancer progression can make
tumor cells more responsive to
malignancy-promoting
ligands such as OPN and result in increased
tumor cell aggressiveness.