Androgen Receptor-Mediated Escape Mechanisms from Androgen Ablation Therapy
Annual rept. 1 Oct 2005-30 Sep 2006
UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES
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Too many prostate-cancer treatments, especially those relying on the suppression of androgen, eventually fail to slow the advance of the disease. One explanation for this situation is the absence of any systematic knowledge on the role and function of the androgen receptor AR in the course of prostate cancer development. Recent findings indicate that the AR is the key master regulator transcription factor that determines disease progression to androgen independence, which ultimately contributes to death from prostate cancer. During the second year of this grant funding, we concentrated our efforts on the understanding of how transcriptional control of the AR at target loci is achieved as the PCa cells escape from androgen ablation therapy to become treatment resistant. We found that androgen-independent PCa cells have evolved three distinctive alterations in AR-mediated transcription. They are increased RNA polymerase initiation and processivity, increased sensitivity to ligand, and locus-wide chromatin remodeling that depended on sustained AR activity. We proposed a link between AR and subsequent polymerase engagements of target loci leading to a memory of transcriptional activity that in turn sustains altered patterns of histone modifications. Armed with such deeper knowledge of the hormonal and receptor requirements as well as mechanisms associated with prostate cancer growth and expansion, we may be able to develop therapies that prolong lives. Understanding the behavior of the AR, as documented above, is a first step in that quest.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research