AR MUTATIONS IN ANDROGEN-INDEPENDENT PROSTATE CANCER
Principal Investigator: Steven Balk
Abstract: Prostate cancer is the most common malignancy in males other than skin cancer and is the second leading cause of cancer death in men. Prostate cancer growth in most patients is androgen dependent, so that removing androgens (androgen ablation) by orchiectomy or the administration of LHRH agonists is a very effective treatment. Unfortunately, most patients develop androgen-independent (AI) prostate cancer within two years, for which there is no effective treatment. The mechanisms by which tumor cells escape androgen ablation and become androgen-independent are unknown. However, several lines of evidence indicate that mutations in the androgen receptor (AR), which mediates the effects of androgens on prostate cells, may be one important mechanism. The specific aims of this project are 1) to determine the frequency and spectrum of AR mutations in AI prostate cancer and 2) to determine the functional significance of these mutations. The AR from a series AI prostate cancer patients will be analyzed by reverse transcription- polymerase chain reaction amplification, using involved bone marrow as the primary source of tumor. Mutations will be identified primarily by DNA sequencing of multiple ARs from each patient. The potential functional significance of AR mutations will be assessed by determining their affinity for a series of steroid hormones and their ability to transactivate a reporter gene linked to an androgen responsive element. Studies will also be initiated to identify drugs which can inhibit mutants ARs. The goal will be to establish whether and by what mechanisms AR mutations play a role in the development of AI prostate cancer. If successful, then these mutant ARs may be useful as targets in the development of new drugs for the treatment of prostate cancer.
Funding Period: 1996-04-01 - 2000-11-30
more information: NIH RePORT
- Androgen receptor remains critical for cell-cycle progression in androgen-independent CWR22 prostate cancer cellsXin Yuan
Hematology Oncology Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA
Am J Pathol 169:682-96. 2006..These results reveal a potentially critical function of AR in androgen-independent PCa that is distinct from its previously described transcriptional or nontranscriptional functions...
- SOX9 is expressed in normal prostate basal cells and regulates androgen receptor expression in prostate cancer cellsHongyun Wang
Cancer Biology Program, Division of Hematology Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Urology Research Laboratory, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA
Cancer Res 67:528-36. 2007..These results indicate that SOX9 in prostate basal cells supports the development and maintenance of the luminal epithelium and that a subset of prostate cancer cells may escape basal cell requirements through SOX9 expression...
- SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasionHongyun Wang
Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Cancer Res 68:1625-30. 2008..These results support important functions of SOX9 in both the development and maintenance of normal prostate, and indicate that these functions contribute to PCa tumor growth and invasion...