In the screening of apoptosis-related genes, an elevated 4.5-kb transcript representing the full-length cDNA of human secreted frizzled-related protein (hsFRP) was cloned. To investigate its possible role in the regulation of cell proliferation, gene expression of hsFRP was examined in human immortalized breast epithelial cell line HBL-100 during growth arrest and apoptosis. Serum deprivation caused G arrest and induction of hsFRP. When serum was re-introduced into the cell culture, the expression of hsFRP declined. Adriamycin treatment induced accumulation of hsFRP mRNA and decrease of beta-catenin. This indicates that the regulation of hsFRP may be involved in the cell-cycle/apoptosis mechanism and possibly in the wnt signaling pathway. hsFRP transcripts were undetectable in cells derived from malignant breast carcinomas, but detectable in 3 immortalized non-malignant breast epithelial cell lines, indicating the involvement of hsFRP in the breast malignant transformation. When tumor and adjacent normal tissues from the same patients were examined, lower expression was found in 5/5 of breast tumors, 2/4 of ovary tumors and 3/5 of kidney tumors. These data suggest the possible involvement of hsFRP in regulation of cell proliferation and breast tumorigenesis.