To determine the functional significance of the endogenous expression of the epidermal growth factor (EGF) and transforming growth factor-alpha genes in T-47D, human breast cancer cells, we have examined the effects of two types of antiproliferative agents, progestins and antiestrogens, on the expression of these growth factors and the effects of exogenous EGF on the antiproliferative action of these agents. Using Northern blot analysis, the regulation of expression of these two genes by the antiproliferative agents, tamoxifen and monohydroxytamoxifen, was examined. In T-47D cells the two antiestrogens did not affect the accumulation of EGF mRNA and decreased the accumulation of TGF alpha mRNA. As we have shown before, the progestin, medroxyprogesterone acetate, increased the level of both EGF mRNA and TGF alpha mRNA in this cell line. The regulation of expression of these endogenous growth factor genes was unrelated to the proliferative behavior of T-47D cells since both antiestrogens and progestins were antiproliferative under the conditions of the experiments. The variant cell line, T-47D-5, had no detectable EGF mRNA and contained about 1/10th the level of TGF alpha mRNA expressed by "wild type" T-47D cells. T-47D-5 cells were 2.5 times more sensitive to the antiproliferative effects of both progestins and antiestrogens when compared to the growth factor expressing T-47D cells. Exogenously added murine EGF was able to decrease slightly the sensitivity of both cell lines to the antiproliferative effects of both progestins and antiestrogens as well as increase the proliferation of T-47D but not T-47D-5 cells. These data suggest that endogenous expression of growth factors may be associated with decreased sensitivity of the cells to growth inhibitory agents.