Prostate cancer is the most commonly diagnosed malignancy in American men. Although there have been improvements in the management of localized lesions, a significant proportion of men initially present with, or subsequently develop, metastatic disease. Using a functional approach, the applicant's group has identified a 70 cM portion of human chromosome 17 that inhibits metastatic colonization of the lung by highly metastatic AT6.1 Dunning rat prostate cancer cells. The applicant has recently identified the mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1) gene as a metastasis-suppressor gene mapped to this region. Specifically, transfection of AT6.1 cells with MKK4/SEK1 reduced the number of overt metastases by approximately 90% compared to transfection controls, without affecting the growth rate of the primary tumors. Further studies demonstrated that suppression by MKK4/SEK1 is due to an inhibitory effect on growth at the metastatic site unrelated to angiogenesis. This work is novel as it provides evidence for a role for signal transduction genes in metastasis suppression and metastatic colonization.
Two specific aims will be pursued to determine the mechanism through which MKK4/SEK1 suppresses metastatic colonization and to establish the role of MKK4/SEK1 dysregulation in prostate cancer metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ET-2 (02))
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Mohla, Suresh
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University of Chicago
Schools of Medicine
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