Control of type II transforming growth factor-β receptor expression by integrin ligation

Ectopic expression of the alpha(5) integrin subunit in cancer cells with little or no endogenous expression of this integrin often results in reduced proliferation as well as reduced malignancy, We now show that inhibition resulting from ectopic expression of alpha(5) integrin is due to induction of autocrine negative transforming growth factor-beta (TGF-beta) activity. MCF-7 breast cancer cells do not express either alpha(5) integrin or type II TGF-beta receptor and hence are unable to generate TGF-beta signal transduction. Ectopic expression of cy,integrin expression enhanced cell adhesion to fibronectin, reduced proliferation, and increased the expression of type II TGF-beta receptor mRNA and cell surface protein. Receptor expression was increased to a higher level in alpha(5) transfectants by growth on fibronectin-coated plates. Induction of type II TGF-beta receptor expression also resulted in the generation of autocrine negative TGF-beta activity because colony formation was increased after TGF-beta neutralizing antibody treatment. Transient transfection with a TGF-beta promoter response element in tandem with a luciferase cDNA into cells stably transfected with cu, integrin resulted in basal promoter activities 5-10-fold higher than those of control cells. Moreover, when alpha(5) transfectants were treated with a neutralizing antibody to either TGF-beta or integrin alpha(5), this increased basal promoter activity was blocked, Autocrine TGF-beta activity also induced 3-fold higher endogenous fibronectin expression in alpha(5) transfectants relative to that of control cells, Re-expression of type II receptor by alpha(5) transfection also restored the ability of the cells to respond to exogenous TGF-beta and led to reduced tumor growth in athymic nude mice. Taken together, these results show for the first time that TGF-beta type II receptor expression can be controlled by alpha(5)beta(1) ligation and integrin signal transduction, Moreover, TGF-beta and integrin signal transduction appear to cooperate in their tumor-suppressive functions.