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

Ectopic expression of the alpha(5) integrin subunit in cancer cells with li ttle or no endogenous expression of this integrin often results in reduced proliferation as well as reduced malignancy, We now show that inhibition re sulting from ectopic expression of alpha(5) integrin is due to induction of autocrine negative transforming growth factor-beta (TGF-beta) activity. MC F-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 transduc tion. Ectopic expression of cy,integrin expression enhanced cell adhesion t o 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 fibrone ctin-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 treatme nt. Transient transfection with a TGF-beta promoter response element in tan dem with a luciferase cDNA into cells stably transfected with cu, integrin resulted in basal promoter activities 5-10-fold higher than those of contro l cells. Moreover, when alpha(5) transfectants were treated with a neutrali zing 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 rel ative 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 exogen ous TGF-beta and led to reduced tumor growth in athymic nude mice. Taken to gether, these results show for the first time that TGF-beta type II recepto r expression can be controlled by alpha(5)beta(1) ligation and integrin sig nal transduction, Moreover, TGF-beta and integrin signal transduction appea r to cooperate in their tumor-suppressive functions.