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Regulation of Growth and Tumorigenicity of Breast Cancer Cells by the Low Molecular Weight GTPase Rad and Nm23¹

Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215 [Y-H. T., D. V., J. Z., J. S. M., C. R. K.]; and Department of Pathology, University of Manitoba, Winnipeg, Manitoba R3E OW3, Canada [Y. N., A. A., P. H. W.]

Rad is the prototypic member of a family of novel Ras-related GTPases that is normally expressed in heart, skeletal muscle, and lung and that has been shown to exhibit a novel form of bi-directional interaction with the nm23 metastasis suppressor. In the present study, we have investigated the expression of Rad in normal and neoplastic breast tissues by Western blot and immunohistochemistry and the functional effect of altered Rad expression in breast cancer cell lines. We found that, although Rad is frequently expressed in normal breast tissue (23/30 Rad+ve), expression is usually lost in adjacent invasive carcinoma (8/30 Rad+ve; P < 0.0001). However, where Rad expression persists in a small proportion of tumors, it is associated with higher grade, larger size, and extensive axillary nodal involvement (n = 48; P = 0.035, P = 0.016, P = 0.022, respectively). Furthermore, Rad is also highly expressed in a breast cancer cell line with high tumorigenic and metastatic potential (MDA-MB231). To further examine the role of Rad in breast cancer, we stably transfected a Rad-ve breast cancer cell line (MDA-MB435). We observed an increase in growth and marked increased colony formation in soft agar in vitro (P < 0.05) and an increase in tumor growth rate in nude mice (P < 0.05). Moreover, coexpression of nm23 with wild-type Rad inhibited the effect of Rad on growth of these cells in culture and markedly inhibited tumor growth in vivo. Additional transfection studies with mutated Rad cDNAs revealed that the growth-promoting effects of Rad appeared to be mediated through its NH₂- and COOH-terminal regions, rather than its GTPase domain, and might involve acceleration of cell cycle transition. These findings suggest that Rad may act as an oncogenic protein in breast tissues and demonstrate a potential mechanism by which interaction between Rad and nm23 may regulate growth and tumorigenicity of breast cancer.

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