Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor)

PC-cell-derived growth factor (PCDGF) is an 88-kDa glycoprotein correspondi ng to the granulin precursor. We have reported that PCDGF was expressed in human breast cancer cells. In estrogen-receptor positive cells, 17-beta -es tradiol (E-2) transcriptionally stimulated PCDGF expression in a dose- and time-dependent fashion. We demonstrate here that PCDGF mediates the mitogen ic effect of E-2 in MCF-7 cells. PCDGF substituted for E-2 to stimulate DNA synthesis. The E-2 mitogenic effect was inhibited in a dose-dependent fash ion by anti-PCDGF neutralizing antibody. Inhibition of PCDGF expression by antisense transfection also inhibited the E-2 mitogenic effect. In contrast , overexpression of PCDGF in MCF-7 cells resulted in cells that were able t o proliferate in the absence of estrogen and were tamoxifen resistant. The PCDGF signaling pathway was examined. Like E-2, PCDGF stimulated mitogen-ac tivated protein kinase activity. PCDGF could substitute for E-2 in stimulat ing cyclin D1 expression. The cyclin D1 stimulation by E-2 was 50% inhibite d by anti-PCDGF antibody. In contrast, PCDGF did not stimulate c-myc expres sion, another molecular target of E-2. We conclude that autocrine PCDGF med iates the E-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.