DIRECT STIMULATION BY ESTROGEN OF GROWTH-FACTOR SIGNAL TRANSDUCTION PATHWAYS IN HUMAN BREAST-CANCER CELLS

Estrogen is thought to stimulate the proliferation of human breast tumors indirectly, through induced production of autocrine polypeptide growth factors. Constitutive production of such growth factors would lead to the loss of 17-beta-estradiol (E2)-dependence that is associated with progression of the disease. Our data, however, do not support this hypothesis and suggest that hormone-dependent breast tumor cell lines like MCF7 do not react to the growth factors which they produce. Moreover, we provide evidence that E2 directly stimulates proliferation by inducing, like many growth factors, the c-fos proto-oncogene. E2 by itself, however, is poorly mitogenic. This may be caused by the lack of induction of genes from the jun family, whose gene products are necessary for dimerization with the c-fos encoded protein, leading to an important step in growth factor signalling pathways; stimulation of TPA responsive element (TRE)-dependent transcriptional activity. In combination with insulin-like growth factors, efficient inducers of c-jun in these cells, E2 synergistically stimulates proliferation and TRE-activity. Constitutive TRE-activation ma lead to loss of E2-dependence.