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Suppression of Metastasis in Human Breast Carcinoma MDA-MB-435 Cells after Transfection with the Metastasis Suppressor Gene, KiSS-1¹

The Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

Based on the observation that chromosome 1q deletions are not infrequent in late-stage human breast carcinomas, we tested whether the recently discovered human melanoma metastasis suppressor gene, KiSS-1, which maps to chromosome 1q32–q41, could suppress metastasis of the human breast carcinoma cell line MDA-MB-435. Parental, vector-only transfectants and KiSS-1 transfectant clones were injected into the mammary fat pads of athymic nude mice and assessed for tumor growth and spontaneous 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 was unaffected, KiSS-1 transfectants spread on immobilized type-IV collagen more rapidly than did control populations. Invasion and motility were unaffected by KiSS-1. Based on the predicted structure of the KiSS-1 protein, our results imply a mechanism whereby KiSS-1 regulates events downstream of cell-matrix adhesion, perhaps involving cytoskeletal reorganization. In addition to its already described role in melanoma, our results show that KiSS-1 also functions as a metastasis suppressor gene in at least some human breast cancers.

¹ Supported by United States Army Medical Research and Materiel Command Grant DAMD-17-49-6152, USPHS Grant CA62168, the National Foundation for Cancer Research, and The Jake Gittlen Memorial Golf Tournament.

² To whom requests for reprints should be addressed, at The Jake Gittlen Cancer Research Institute (C7810, MB-059), The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033. Phone: (717) 531-5633; Fax: (717) 531-5634; E-mail: drw9@psu.edu.

Received 3/17/97. Accepted 4/30/97.

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