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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089569-04
Application #
6747963
Study Section
Special Emphasis Panel (ZRG1-ET-2 (02))
Program Officer
Sathyamoorthy, Neeraja
Project Start
2001-04-04
Project End
2006-03-31
Budget Start
2004-04-19
Budget End
2005-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$303,301
Indirect Cost
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Clark, Robert; Krishnan, Venkatesh; Schoof, Michael et al. (2013) Milky spots promote ovarian cancer metastatic colonization of peritoneal adipose in experimental models. Am J Pathol 183:576-91
Bainer, Russell O; Veneris, Jennifer Taylor; Yamada, S Diane et al. (2012) Time-dependent transcriptional profiling links gene expression to mitogen-activated protein kinase kinase 4 (MKK4)-mediated suppression of omental metastatic colonization. Clin Exp Metastasis 29:397-408
Krishnan, Venkatesh; Stadick, Nathan; Clark, Robert et al. (2012) Using MKK4's metastasis suppressor function to identify and dissect cancer cell-microenvironment interactions during metastatic colonization. Cancer Metastasis Rev 31:605-13
Szmulewitz, Russell Z; Clark, Robert; Lotan, Tamara et al. (2012) MKK4 suppresses metastatic colonization by multiple highly metastatic prostate cancer cell lines through a transient impairment in cell cycle progression. Int J Cancer 130:509-20
Thobe, Megan N; Clark, Robert J; Bainer, Russell O et al. (2011) From prostate to bone: key players in prostate cancer bone metastasis. Cancers (Basel) 3:478-93
Thiolloy, Sophie; Rinker-Schaeffer, Carrie W (2011) Thinking outside the box: using metastasis suppressors as molecular tools. Semin Cancer Biol 21:89-98
Knopeke, Matthew T; Ritschdorff, Eric T; Clark, Robert et al. (2011) Building on the foundation of daring hypotheses: using the MKK4 metastasis suppressor to develop models of dormancy and metastatic colonization. FEBS Lett 585:3159-65
Shoushtari, Alexander N; Szmulewitz, Russell Z; Rinker-Schaeffer, Carrie W (2011) Metastasis-suppressor genes in clinical practice: lost in translation? Nat Rev Clin Oncol 8:333-42
Khan, Shaheena M; Funk, Holly M; Thiolloy, Sophie et al. (2010) In vitro metastatic colonization of human ovarian cancer cells to the omentum. Clin Exp Metastasis 27:185-96

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