SUPPRESSION OF METASTASIS IN HUMAN BREAST-CARCINOMA MDA-MB-435 CELLS AFTER TRANSFECTION WITH THE METASTASIS SUPPRESSOR GENE, KISS-1

Based on the observation that chromosome 1q deletions are not infreque nt in late-stage human breast carcinomas, we tested whether the recent ly discovered human melanoma metastasis suppressor gene, KiSS-1, which maps to chromosome 1q32-q41, could suppress metastasis of the human b reast carcinoma cell line MDA-MB-435. Parental, vector-only transfecta nts and KiSS-1 transfectant clones were injected into the mammary fat pads of athymic nude mice acid assessed for tumor growth and spontaneo us metastasis to regional lymph nodes and lungs. Expression of KiSS-1 reduced metastatic potential by 95% compared to control cells but did not suppress tumorigenicity. Metastasis suppression correlated with a decreased clonogenicity in soft (0.3%) and hard (0.9%) agar. Although the overall rate of cell adhesion to extracellular matrix components w as unaffected, KiSS-1 transfectants spread on immobilized type-IV coll agen more rapidly than did control populations. Invasion and motility were unaffected by KiSS-1. Based on the predicted structure of the KiS S-1 protein, our results imply a mechanism whereby KiSS-1 regulates ev ents downstream of cell-matrix adhesion, perhaps involving cytoskeleta l reorganization. In addition to its already described role in melanom a, our results show that KiSS-1 also functions as a metastasis suppres sor gene in at least some human breast cancers.