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Antitumor Activity of the Novel Human Breast Cancer Growth Inhibitor, Mammary-derived Growth Inhibitor-related Gene, MRG¹

Departments of Pediatrics [Y. E. S., G. X., Y. E. L.], Pathology [Y. E. S., A. F.], and Surgery [J. M. C.], Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040; Human Genome Sciences, Inc., Rockville, Maryland 20850-3338 [J. N., G. Y., J. S., L. X., M. Z., R. G.]; Beijing Institute for Cancer Research, Beijing, China [J. L.]; Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [B. B. A.]; and National Institute for Biological Standards and Control, Potters Bar, United Kingdom [A. M.]

A novel human tumor growth inhibitor was identified by differential cDNA sequencing. The predicted amino acid sequence of this tumor-suppressing factor has a significant sequence homology to mouse mammary-derived growth inhibitor and thus was named mammary-derived growth inhibitor-related gene (MRG). MRG was found to be expressed in normal and benign human breast tissues but not in breast carcinomas. In situ hybridization analysis demonstrated a stage-specific MRG expression as follows. MRG was barely detectable in breast carcinomas, showed partial and weak expression in benign hyperplasia, but was expressed at a high level in normal breast epithelial cells. To determine if MRG can modulate in vivo growth of human breast cancers, we transfected a full-length MRG cDNA into MDA-MB-231 human breast cancer cells and studied the orthotopic growth of MRG transfectants versus control transfectants in the mammary fat pad of athymic nude mice. Overexpression of MRG in human breast cancer cells significantly suppressed cell proliferation in vitro and tumor growth in an orthotopic nude mouse model. These results suggest that MRG has tumor-suppressing activity, and the loss of MRG expression may be involved in the development and progression of breast cancer.

¹ This work was supported in part by Grant CA68064-01 from the NIH, Grant DAMD17-94-J-4229 from the United States Department of the Army, and Helen and Irving Schneider. The first two authors contributed equally to this work.

² To whom requests for reprints should be addressed, at Pediatric Research Center, Schneider Children's Hospital, Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, NY 11040. Phone: (718) 470-3086; Fax: (718) 470-6744; E-mail: shi@lij.edu.

Received 3/17/97. Accepted 6/12/97.

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