PC-cell-derived growth factor (PCDGF) is an 88-kDa glycoprotein corresponding to the granulin precursor. We have reported that PCDGF was expressed in human breast cancer cells. In estrogen-receptor positive cells, 17-[Beta]-estradiol ([E.sub.2]) transcriptionally stimulated PCDGF expression in a dose- and time-dependent fashion. We demonstrate here that PCDGF mediates the mitogenic effect of [E.sub.2] in MCF-7 cells. PCDGF substituted for [E.sub.2] to stimulate DNA synthesis. The [E.sub.2] mitogenic effect was inhibited in a dose-dependent fashion by anti-PCDGF neutralizing antibody. Inhibition of PCDGF expression by antisense transfection also inhibited the [E.sub.2] mitogenic effect. In contrast, overexpression of PCDGF in MCF-7 cells resulted in cells that were able to proliferate in the absence of estrogen and were tamoxifen resistant. The PCDGF signaling pathway was examined. Like [E.sub.2], PCDGF stimulated mitogen-activated protein kinase activity. PCDGF could substitute for [E.sub.2] in stimulating cyclin D1 expression. The cyclin D1 stimulation by [E.sub.2] was 50% inhibited by anti-PCDGF antibody. In contrast, PCDGF did not stimulate c-myc expression, another molecular target of [E.sub.2]. We conclude that autocrine PCDGF mediates the [E.sub.2] mitogenic effect via stimulation of cyclin D1. These studies provide information on estrogen action and identify an autocrine molecular target in human breast cancer cells.