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2004 Scientific Report

prostate carcinomas. In

prostate carcinomas. In some cases, this is associated with activating mutations in the ß-catenin genes, while in others, a loss of APC has been demonstrated. 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 linkage between the activation of Wnt signaling and bone growth, and the fact that ß- 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 the phenotype of advanced prostate cancer. We are trying to understand the role of the Wnt signaling pathway in normal prostate development. Analysis of mice carrying compound mutations in Lrp5 and Lrp6 revealed the presence of abnormal prostate lobes. We are furthering this analysis by creating mice with a prostate-specific deletion of ß-catenin. We have also created mice with a prostate-specific deletion of the Apc gene. Preliminary analysis shows that these mice develop early-onset prostate cancer. We are preparing to analyze mice at various ages to determine the ability of Apcdeficient prostate tumors to metastasize. We will also assess the ability of Apc-deficient prostate tumors to synergize with other genetic alterations to produce higher-grade prostate carcinoma. Our ultimate goal is to test whether loss of activation of ß-catenin signaling can lead to a mouse model of prostate cancer with skeletal metastases. Wnt signaling in mammary development and cancer We are also examining the roles of Lrp5 and Lrp6 in normal mammary development. We have found that mice lacking these genes have delays in the normal development process. We are currently assessing the temporal and spatial organization of Lrp6 and Lrp5 expression during mammary development. We are also addressing the relative roles of Lrp6 and Lrp5 in Wnt1-induced mammary carcinogenesis. We have found that a deficiency of Lrp5 dramatically inhibits the development of Wnt1-induced mammary tumors. In addition, the tumors that do develop are altered in their morphology. Current work aims to determine the mechanisms that explain these findings. Interestingly, the development of precancerous hyperplasia in the mammary gland still occurs in Lrp5-deficient animals. In vitro studies of the Wnt receptor complex The reception of Wnt signals is regulated at many levels. The completion of the Human Genome Project has shown that there are 19 different genes that encode Wnt proteins, 9 that encode Frizzled proteins, and the Lrp5 and Lrp6 genes. In addition, there are several proteins that can inhibit Wnt signaling by binding to components of the receptor complex and interfering with normal signaling; these include Dickkopfs (Dkks) and Frizzled-related proteins (FRPs). One of the long-term goals of our laboratory is to understand how specificity is generated for the different signaling pathways. A B C Figure 1. Disregulation of Wnt signaling specifically in osteoblasts results in dramatic changes in bone development. Shown in Panel A is a hematoxylin and eosin–stained section through a thoracic vertebra of a one-month-old normal mouse. Sections from the same region of bone in age-matched mice carrying an osteoblast-specific deletion of ß-catenin (B) and Apc (C) are shown. Osteoblastspecific deletion of either ß-catenin or Apc causes death within four weeks of birth. This lethality is associated with a dramatic reduction of bone in the ß-catenin mutants (B) and a vast overgrowth of bone in the absence of Apc (C). 60

External Collaborators Yi Li, Baylor Breast Center, Houston, TX Michael T. Lewis, Baylor Breast Center, Houston, TX Matthew Warman, Case Western Reserve University, Cleveland, OH Thomas Clemens, University of Alabama – Birmingham Mary Bouxsein, Beth Israel Deaconess Medical Center, Boston, Massachusetts Marie Faugere, University of Kentucky, Lexington Wade Bushman, University of Wisconsin – Madison Charles Turner, Indiana University – Purdue University, Indianapolis Kay Macleod, University of Chicago, Illinois Recent Publications Bromberg-White, Jennifer L., Craig P. Webb, Veronique S. Patacsil, Cindy K. Miranti, Bart O. Williams, and Sheri L. Holmen. 2004. Delivery of short hairpin RNA sequences using a replication-competent avian retroviral vector. Journal of Virology 78(9): 4914-4916. Holmen, Sheri L., Adrian Salic, Cassandra R. Zylstra, Marc W. Kirschner, and Bart O. Williams. 2002. A novel set of Wnt-Frizzled fusion proteins identifies receptor components that activate β- catenin-dependent signaling. Journal of Biological Chemistry 277(38): 34727–34735. Takahashi, Masayuki, Ximing J. Yang, Todd T. Lavery, Kyle A. Furge, Bart O. Williams, Maria Tretiakova, Anthony Montag, Nicholas J. Vogelzang, Gian G. Re, A. Julian Garvin, Stefan Söderhäll, Susumu Kagawa, Debra Hazel-Martin, Agneta Nordenskjöld, and Bin Tean Teh. 2002. Gene expression profiling of favorable histology Wilms tumors and its correlation with clinical features. Cancer Research 62(22): 6598–6605. From left to right: back row, Williams, Charbonneau, Zylstra front row, Lindvall-Weinreich, Giambernardi, Holmen 61

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