Stimulation of epithelial membrane antigen expression by transforming growth factor-beta in normal and...

Transforming growth factor-beta (TGF beta) appears to play a role in regulating the expression of tissue-specific proteins in human mammary epithelial cells (HMEC), regardless of the state of malignant transformation. We demonstrated this by utilizing a series of normal, immortalized, and oncogene-transformed (SV40 T and v-Ha-ras) HMEC derived from one individual, and assaying for expression of a milk fat globule/epithelial membrane antigen (EMA) reactive with E29/EP1 monoclonal antibody. EMA was increased by TGF beta in all HMEC examined. This effect appeared to be dose-dependent between 5 and 15 ng/ml in the normal, immortalized, and v-Ha-ras-transformed cells but saturated at 5 ng/ml in the SV40 T-transformed cells. The SV40 T-transformed cells showed both enhanced basal expression of EMA and increased sensitivity to TGF beta stimulation of EMA expression. The degree of increase in EMA induced by TGF beta was proportional to the level of basal expression in each cell type and appeared to be unrelated to either the number of high affinity TGF beta receptors, or the relative sensitivity to growth inhibition by TGF beta. Therefore, the TGF beta effect on EMA appears to be modulated at a level beyond receptors in these cells. EMA expression was also stimulated by sodium butyrate and dexamethasone (both differentiating agents) in some of the HMEC. The effect of butyrate on EMA expression is consistent with previous findings in which butyrate selectively enhanced production of milk fat globule antigens in the breast tumor cell line MCF-7, ZR-75-1, MDA-MB-134, and MDA-MB-468 cells. The coupled effects of TGF beta and SV40 T-transformation in enhancing the expression of EMA, and the possible effect of SV40 T increasing the responsiveness to TGF beta, may provide a new model for the study of the effect of growth factors in regulating specific gene expression in human breast epithelial cells.