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Prolonged Exposure to Reduced Levels of Androgen Accelerates Prostate Cancer Progression in Nkx3.1; Pten Mutant Mice

¹ Center for Advanced Biotechnology and Medicine and ² Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey and ³ Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio

Requests for reprints: Cory Abate-Shen, Columbia University College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, 1130 St. Nicholas Ave., Room 217A, New York, NY 10032. Phone: 212-851-4731; E-mail: ca2319{at}columbia.edu.

In this report, we have investigated the relationship between androgen levels and prostate tumorigenesis in Nkx3.1; Pten mutant mice, a genetically engineered mouse model of human prostate cancer. By experimentally manipulating serum levels of testosterone in these mice for an extended period (i.e., 7 months), we have found that prolonged exposure of Nkx3.1; Pten mutant mice to androgen levels that are 10-fold lower than normal (the "Low-T" group) resulted in a marked acceleration of prostate tumorigenesis compared with those exposed to androgen levels within the reference range (the "Normal-T" group). We found that prostate tumors from the Low-T mutant mice share a similar gene expression profile as androgen-independent prostate tumors from these mutant mice, which includes the deregulated expression of several genes that are up-regulated in human hormone-refractory prostate cancer, such as Vav3 and Runx1. We propose that exposure to reduced androgens may promote prostate tumorigenesis by selecting for molecular events that promote more aggressive, hormone-refractory tumors. [Cancer Res 2007;67(19):9089–96]

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