A stable cyclized 9-mer peptide (cP) containing the active site of cc-alpha fetoprotein (alpha FP) has been shown to be effective for prevention of estrogen-stimulated tumor cell proliferation in culture or of xenographt growth in immunodeficient mice. cP does not block 17 beta-estradiol (E-2) binding to its receptors, but rather appears to interfere with intracellular processing of the signal that supports growth. To obtain insight on that mechanism we studied the effect of cP on the proliferation of MCF-7 cells in culture. Proliferation in the presence of 2 mu M E-2 is decreased up to 40% upon addition of 2 mu g ml(-1) cP to the medium; the presence of cP did not increase cell death. cP reduced also the proliferation of estrogen-dependent ZR75-1 cells but had no effect on autonomous MDA-MB-231 cells. cP did not modify the number of binding sites for labeled E-2 or affected cell death. We detected increased nuclear p21(Cip1) immunoreactivity after cP treatment. Our results suggest that cP acts via p21Cip1 to slow the process of MCF-7 cells through the cycle.