In view of the tumor suppressor role of the transforming growth factor- (TGF) type II receptor (RII), the identification and characterization of agents that can induce the expression of this receptor are of potential importance to the development of chemoprevention approaches as well as treatment of cancer. To date, the identification of exogenous agents that control RII expression has been rare. We demonstrated that proliferation of MCF-7 early passage cells (MCF-7 E), which express RII and are sensitive to TGF growth inhibition activity, was significantly inhibited by vitamin D 3 and its analogue EB1089. In contrast, proliferation of MCF-7 late passage cells (MCF-7 L), which have lost cell surface RII and are resistant to TGF, was not affected by these two compounds. TGF-neutralizing antibody was able to block the inhibitory effect on MCF-7 E cells by these compounds, indicating that treatment induced autocrine-negative TGF activity. An RNase protection assay showed approximately a 3-fold induction of the RII mRNA, while a receptor cross-linking assay revealed a 3-4-fold induction of the RII protein. In contrast, there was no change in either RII mRNA or protein in the MCF-7 L cells.
Transforming growth factor- (TGF)1 comprises a family of hormone-like polypeptides that affects cell growth, adhesion, and differentiation (1). They act as growth inhibitors for most epithelial cells and some cancer cells. Two pathways are primarily involved in mediating effects of TGF on cell growth and differentiation. One pathway involves blockade of cell cycle transit, while the other involves alteration of the extracellular matrix environment.TGFs elicit their effects by binding to cell surface receptors. Three major types of receptors have been shown to be present in most TGF-responsive cell lines. They are designated as type I (RI), type II (RII), and type III (RIII), respectively. RIII is a 280 -330-kDa glycoprotein that has no functional signaling domain but rather serves as a ligand storage protein and presents TGF to the signaling receptors (2). RI and RII, which are glycoproteins of ϳ55 and 85 kDa, respectively, form a heteromeric receptor complex. Both are serine/threonine kinases, and each appears to be indispensable for TGF signaling (3-5). The direct involvement of both RI and RII in conferring TGF effects indicates that loss of either of the functional receptors would contribute to loss of autocrine TGF activity. Loss of negative autocrine TGF activity results in a growth advantage caused by an imbalance in positive and negative regulators, possibly leading to tumor formation and progression (6, 7). Recent evidence has shown a loss of RII is often associated with the failure to respond to autocrine and exogenous TGF. We have previously demonstrated that re-expression of this receptor in an RII-deficient breast cancer cell line (late passage MCF-7) leads to restoration of TGF sensitivity and reduced malignancy in athymic nude mice (6). In addition, it has been shown that mutational inactivation of...