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Mitogen-activated Protein Kinase Kinase 4 (MKK4) Acts as a Metastasis Suppressor Gene in Human Ovarian Carcinoma¹

Department of Obstetrics and Gynecology, Section of Gynecologic Oncology [S. D. Y., Y. H., S. A.], Section of Urology, Department of Surgery, The Committee on Cancer Biology [D. J. V. G., D. B., C. W. R-S.], Department of Biochemistry and Molecular Biology, Markey Molecular Medicine Program [J. A. H.], Department of Pathology [A. M.], and Department of Health Studies [T. K., D. H.], University of Chicago, Chicago, Illinois, and Department of Pathology, Long Beach Memorial Medical Center, Long Beach, California 90806 [J. R.]

Despite improvements in chemotherapy and the recognition that aggressivesurgical cytoreduction is beneficial, the majority of patients diagnosed with ovarian cancer will die as a result of metastatic disease. The molecular changes associated with acquisition of metastatic ability in ovarian cancer are poorly understood. We hypothesize that metastasis suppressor gene inactivation or down-regulation plays a role in ovarian cancer progression.

Mitogen-activated protein kinase kinase 4 (MKK4), a member of the stress-activated protein kinase signaling cascade, has been identified recently as a metastasis-suppressor gene. An immunohistochemical approach was taken to test the possibility that MKK4 dysregulation occurs during the development of clinical ovarian cancer metastases. MKK4 expression was evaluated in normal and metastatic ovarian tissues. Normal ovarian epithelial cells showed high intensity staining for MKK4, whereas metastatic tissues showed a statistically significant decrease in expression. These results support a role for MKK4 dysregulation in the development of clinical disease.

A functional approach was taken to test the ability of MKK4 to suppress metastatic colonization, the process whereby disseminated cancer cells lodge and grow at a secondary site in vivo. The SKOV3ip.1 human ovarian cancer cell line was chosen for these studies because it lacks endogenous MKK4 expression but retains both upstream and downstream components of the signaling cascade of MKK4. Ectopic expression of MKK4 in these cells, when injected into female SCID mice, suppressed the number of overt metastatic implants by nearly 90%. Furthermore, MKK4 expression increased the life span of the animals by 70%. Taken together, these data support a role for MKK4 in the suppression of metastatic colonization in ovarian cancer.

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