Resistance to transforming growth factor β and activin due to reduced receptor expression in human breast tumor cell lines

Loss of sensitivity to growth inhibition by transforming growth factor (TGF)-β is a phenomenon often observed in human epithelial tumor cells and is linked to malignant progression. We tested a panel of estrogen receptor (ER)-positive and -negative breast cell fines for their sensitivity to TGF- β and a related member of the TGF-β superfamily, activin. Both TGF-β- sensitive (MCF7, Hs57BT, and BT20) and -resistant (two T47D variants, ZR75- 1, MDA-MB231, and MDA-MB468) cell lines were found, with no strict correlation between ER content and sensitivity to TGF-β. In contrast, all four ER-positive cell lines were inhibited by activin A, whereas the ER- negative lines were not. To examine whether resistance to TGF-β and activin resulted from the absence of the corresponding receptors, mRNA expression of the types I and II receptors was studied. TGF-β receptor II was not expressed in the two T47D variants and was low in ZR75-1 cells. Upon stable transfection of the TGF-β receptor II in one of the T47D variants, sensitivity to TGF-β1 and TGF-β2 was restored with respect to inhibition of anchorage-dependent and -independent proliferation, indicating that other signal transduction components are functionally intact. Sensitivity to TGF- β in the transfectants was dependent on the expression level of the newly introduced receptor. Resistance to activin in the ER-negative cell lines could be explained in BT20 and Hs578T cells, but not in MDA-MB231 and MDA- MB468, by low activin receptor expression. These results show that resistance to TGF-β and activin is often, but not always, due to reduced expression of the signaling receptor in breast cancer cells. The activin resistance of ER- negative breast tumor cells may be involved in their increased malignancy compared with ER-positive cells.