Carrie Rinker-Schaeffer, Ph.D.

Identification of Metastasis-Suppressor Genes for Prostate and Breast Cancers

Research Summary

Following dissemination from a primary tumor, viable cancer cells that lodge at secondary sites (2 sites) can persist for extended periods of time before going on to form clinically detectable disease. It is puzzling why tumor cells that have lost checkpoint control of the cell cycle and evaded death at the 1 tumor site should fail to grow at remote sites in both experimental models and patients. No one knows how such cells ultimately initiate growth and complete the process of metastatic colonization which can ultimately lead to death. Previously we identified a novel function for MKK4/JNKK1, as a metastasis-suppressor gene for prostate cancer. MKK4/JNKK1 is a dual-specificity kinase that activates the JNK and p38 MAP kinases in response to extracellular stimuli. We have recently shown that ectopic expression of MKK4/JNKK1 results in the context-dependent suppression of metastatic colonization, and that MKK4/JNKK1 protein is down-regulated in clinical disease. Our laboratory is now investigating three general lines of study: (1) Developing a detailed understanding of he signaling events and mechanisms involved in the survival and ultimate induction of growth of disseminated prostate, ovarian and breast cancer cells at metastatic sites; (2) Testing the effect of MKK4/JNKK1 s metastasis suppressor activity in the regulation of cell cycle progression and cell division in disseminated prostate, ovarian and breast cancer cells at metastatic sites; and (3) Exploring the potential contribution of societal interactions which may enable groups of cells to colonization metastatic sites more efficiently that single cells.

Selected Papers

Kauffman EC, Robinson VL, Stadler WM, Sokoloff MH, Rinker-Schaeffer CW. (2003). Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site. J Urol. 169: 1122-33.

Vander Griend DJ, Rinker-Schaeffer CW. (2004). A New Look at an Old Problem: The Survival and Organ-Specific Growth of Metastases Science STKE 2004, pe4.

Vander Griend DJ, Kocherginsky M, Hickson JA, Stadler WM, Lin A, Rinker-Schaeffer CW. (2005). Suppression of Metastatic Coloniztion by the Context-Dependent Activation of JNK Kinases JNKK1/MKK4 and MKK7. Cancer Res 65, 10984-10991.

Hickson JA, Huo D, Vander Griend DJ, Lin A, Rinker-Schaeffer CW, Yamada SD. (2006). The p38 Kinase MKK4 and MKK6 Suppress Metastatic Colonization in Human Ovarian Cancer. Cancer Res.