This proposal is designed to allow the candidate to achieve scientific independence as a clinical investigator in the hormonal therapy of cancer, specifically prostate cancer, through an intensive basic research experience involving analysis of androgen receptor associated proteins in prostate cancer. Prostate cancer is the most common non-cutaneous malignancy of men and the second leading cause of male cancer related deaths. Most men with cancer that has spread beyond the prostate will at some point require androgen ablative therapy (AAT) with leuprolide, DES, or orchiectomy. Although AAT is one of the most effective palliative therapies in medical oncology, most men become refractory to AAT within 12-18 months. The long-term goal of this project is the elucidation of the mechanisms by which the androgen receptor (AR) functions as a ligand dependent transcription factor to support the growth of prostate cancer. A detailed understanding of AR function in prostate cancer should lead to improvements in the hormonal therapy of prostate cancer. Analogous to other members of the steroid receptor superfamily, nuclear cofactors or adapters are likely required for AR activation of gene transcription. The central hypothesis to be tested by this proposal is that androgen receptor associated proteins (ARAPs), which bind the AR only in the presence of androgens, exist in androgen dependent cells, and that these proteins may play a significant role in androgen dependent signal transduction. In addition, disruption of these proteins or their interaction with the AR may be involved in the development of hormone independence in prostate cancer. Recent studies of the estrogen receptor (ER) have identified two estrogen receptor associated proteins (ERAPs), ERAP14O and ERAP160, important in the ligand dependent transactivation function of the ER in breast cancer. In addition, the cDNA encoding ERAP14O has been cloned. These proteins were found on the basis of their ability to associate with the ER hormone binding domain (ER-HBD) in a hormone dependent manner. In a manner similar to the experiments performed to find ERAPs, ARAPs will be isolated on the basis of their ability to bind the AR in a hormone-dependent manner. Their hormone and tissue specificity will be analyzed, and the cDNAs encoding them will be cloned. The precise tissue and ligand specificity of the cloned ARAPs will be determined at the protein and the mRNA level. Potentially critical amino acid residues of the AR involved in ARAP binding will be determined. Finally, ARAP mRNA and protein expression, ARAP interaction with the AR, and ARAP gene structure will be determined for a panel of prostate cancer specimens. It is hoped that a detailed understanding of AR function in molecular terms, specifically in terms of proteins which may transduce its signal, may provide new substrates for the development of more effective therapies for prostate cancer.
| Peters, D G; Kassam, A B; Yonas, H et al. (1999) Comprehensive transcript analysis in small quantities of mRNA by SAGE-lite. Nucleic Acids Res 27:e39 |
| Brufsky, A; Fontaine-Rothe, P; Berlane, K et al. (1997) Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate. Urology 49:913-20 |
