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Clinical-Translational Approaches to the Nm23-H1 Metastasis Suppressor

Authors' Affiliations: ¹ Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland and ² Division of Hematology/Oncology, Indiana University, Indianapolis, Indiana

Requests for reprints: Patricia S. Steeg, Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Room 1122, 37 Convent Drive, Bethesda, MD 20892. Phone: 301-402-2732; Fax: 301-402-8910; E-mail: steegp{at}mail.nih.gov.

Abstract

Nm23-H1 significantly reduces metastasis without effects on primary tumor size and was the first discovered metastasis suppressor gene. At least three mechanisms are thought to contribute to the metastasis-suppressive effect of Nm23-H1: (a) its histidine kinase activity toward ATP-citrate lyase, aldolase C, and the kinase suppressor of ras, with the last inactivating mitogen-activated protein kinase signaling; (b) binding proteins that titer out "free" Nm23-H1 and inhibit its ability to suppress metastasis; and (c) altered gene expression downstream of Nm23-H1, particularly an inverse association with the lysophosphatidic acid receptor endothelial differentiation gene-28 (EDG2). Most metastasis suppressor genes, including Nm23-H1, affect metastatic colonization, which is the outgrowth of tumor cells in distant locations; therefore, they are of high translational interest. A phase II trial is ongoing to test the hypothesis that a compound, high-dose medroxyprogesterone acetate (MPA), used as an unconventional gluocorticoid, will stimulate breast cancer cells to reexpress Nm23-H1 and limit subsequent metastatic colonization.