The study investigates the mechanism by which estradiol promotes cell proliferation in MCF-7 breast cancer cells. Under conditions of estradiol-dependent growth, estradiol treatment triggers rapid and transient activation of mitogen-activated (MAP) kinases erk-1 and erk-2, increases the active form of p21ras, tyrosine phosphorylation of Shc and p190 protein, and induces association of p190 with p21ras-GAP. The activation of these pathways is similar to that induced by peptide mitogens. Introduction of the human wild-type 67 kDa estradiol receptor cDNA into Cos cells is required for estradiol responsiveness in terms of erk-2 activity. This finding, along with the inhibition of estradiol's stimulatory effect on each step of the pathway by the pure anti-estrogen ICI 182 780, confirms that the classic estradiol receptor is responsible for the transduction pathway activation. In vitro experiments with c-src show that the estradiol receptor activates c-src, and this activation requires hormone occupancy of the receptor. These results suggest that c-src is an initial and integral part of the signaling events mediated by the estradiol receptor.The study investigates the mechanism by which estradiol promotes cell proliferation in MCF-7 breast cancer cells. Under conditions of estradiol-dependent growth, estradiol treatment triggers rapid and transient activation of mitogen-activated (MAP) kinases erk-1 and erk-2, increases the active form of p21ras, tyrosine phosphorylation of Shc and p190 protein, and induces association of p190 with p21ras-GAP. The activation of these pathways is similar to that induced by peptide mitogens. Introduction of the human wild-type 67 kDa estradiol receptor cDNA into Cos cells is required for estradiol responsiveness in terms of erk-2 activity. This finding, along with the inhibition of estradiol's stimulatory effect on each step of the pathway by the pure anti-estrogen ICI 182 780, confirms that the classic estradiol receptor is responsible for the transduction pathway activation. In vitro experiments with c-src show that the estradiol receptor activates c-src, and this activation requires hormone occupancy of the receptor. These results suggest that c-src is an initial and integral part of the signaling events mediated by the estradiol receptor.