2009 Scientific Report

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Van Andel Research Institute | Scientific Report Wnt signaling in prostate development and cancer Two hallmarks of advanced prostate cancer are the development of skeletal osteoblastic metastasis and the ability of the tumor cells to become independent of androgen for survival. The association of Wnt signaling with bone growth, plus the fact that b-catenin can bind to the androgen receptor and make it more susceptible to activation with steroid hormones other than DHT, make Wnt signaling an attractive candidate for explaining some phenotypes associated with advanced prostate cancer. We have created mice with a prostate-specific deletion of the Apc gene. These mice develop fully penetrant prostate hyperplasia by four months of age, and these tumors progress to frank carcinomas by seven months. We have found that these tumors initially regress under androgen ablation but show signs of androgen-independent growth some months later. VARI mutant mouse repository With support from the Institute, our laboratory maintains a repository of mutant mouse strains to support the general development of animal models of human disease. External Collaborators Bone development Mary Bouxsein, Beth Israel Deaconness Medical Center, Boston, Massachusetts Thomas Clemens, University of Alabama–Birmingham Marie-Claude Faugere, University of Kentucky, Lexington Fanxin Long and David Ornitz, Washington University, St. Louis, Missouri Merry Jo Oursler, Mayo Clinic, Rochester, Minnesota Matthew Warman, Harvard Medical School, Boston, Massachusetts Prostate cancer Wade Bushman, University of Wisconsin–Madison Valeri Vashioukhin, Fred Hutchinson Cancer Research Center, Seattle, Washington Mammary development Caroline Alexander, University of Wisconsin–Madison Yi Li, Baylor Breast Center, Houston, Texas Metabolic syndrome Tim Garvey, University of Alabama-Birmingham Jiandie Lin and Ormond MacDougald, University of Michigan, Ann Arbor Other organ systems/mechanisms of Wnt signaling Kathleen Cho and Eric Fearon, University of Michigan, Ann Arbor Kang-Yell Choi, Yansei University, Seoul, South Korea Silvio Gutkind, National Institute of Dental and Craniofacial Research, Bethesda, Maryland Kun-Liang Guan, University of California, San Diego Richard Lang and Aaron Zorn, Cincinnati Children’s Hospital Medical Center, Ohio Malathy Shekhar, Wayne State University, Detroit, Michigan 70
VARI | 2009 Recent Publications Li, Y., A. Ferris, B.C. Lewis, S. Orsulic, B.O. Williams, E.C. Holland, and S.H. Hughes. In press. The RCAS/TVA somatic gene transfer method in modeling human cancer. In Mouse Models for Cancer Research, J. Green and T. Ried, eds., Springer Verlag. Williams, B.O., and K.L. Insogna. 2009. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling. Journal of Bone and Mineral Research 24(2): 171–178. Badders, Nisha M., Shruti Goel, Rod J. Clark, Kristine S. Klos, Soyoung Kim, Anna Bafico, Charlotta Lindvall, Bart O. Williams, and Caroline M. Alexander. 2009. The Wnt receptor, Lrp5, is expressed by mouse mammary stem cells and is required to maintain the basal lineage. PLoS One 4(8): e6594. Castilho, Rogerio M., Cristiane H. Squarize, Lewis A. Chodosh, Bart O. Williams, and J. Silvio Gutkind. 2009. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell 5(3): 279–289. Lindvall, Charlotta, Cassandra R. Zylstra, Nicole Evans, Richard A. West, Karl Dykema, Kyle A. Furge, and Bart O. Williams. 2009. The Wnt co-receptor Lrp6 is required for normal mouse mammary gland development. PLoS One 4(6): e5813. Chen, Jindong, Kunihiko Futami, David Petillo, Jun Peng, PengFei Wang, Jared Knol, Yan Li, Sok Kean Khoo, Dan Huang, Chao-Nan Qian, et al. 2008. Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia. PLoS One 3(10): e3581. VanKoevering, K.K., and B.O. Williams. 2008. Transgenic mouse strains for conditional gene deletion during skeletal development. IBMS BoneKEy 5(5): 151–170. Zylstra, C.R., C. Wan, K.K. VanKoevering, A.K. Sanders, C. Lindvall, T.L. Clemens, and B.O Williams. 2008. Gene targeting approaches in mice: assessing the roles of LRP5 and LRP6 in osteoblasts. Journal of Muskuloskeletal & Neuronal Interactions 8(4): 291–293. Standing, from left: Zhong, Sanders, Lindvall, Lake, Elumalai; seated, from left: Diegel, Williams 71
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