Carcinoma of the prostate is one of the most common malignancies affecting men in the United States. It is estimated in 2003 that 220,900 new cases will be diagnosed and 28,900 men will die of this disease. Around one third of men relapse after prostatectomy from a previously undetected metastatic disease. The primary treatment for metastatic cancer is the removal of testicular androgens by orchiectomy or treatment with gonadotropin-releasing hormone analogs. Androgen receptor (AR) antagonists are frequently added to androgen ablation therapy to block the effects of androgens produced by the adrenal gland. Metastatic prostate cancer responds to androgen-deprivation therapy for a variable period of time, but eventually resumes growth despite castrate levels of androgen. This state of disease termed "androgen-independent" prostate cancer is characterized by the expression of the AR and AR-regulated genes such as prostate-specific antigen. Understanding the molecular mechanisms of AR reactivation will greatly improve our ability to treat advanced prostate cancer.

The family of epidermal growth factor receptors has been implicated in the progression of prostate cancer to the androgen-independent state. This family of cell surface receptors comprises four members (ErbB1, ErbB2, ErbB3, ErbB4) that share certain receptor ligands and interact with each other through the formation of receptor heterodimers. It appears that signals originating from and/or transmitted through this network regulate the function of the AR at low levels of androgen. Using established models of human prostate cancer, I have recently been able to show that a small molecule inhibitor targeting the family members ErbB1 and ErbB2 impairs the growth of androgen-independent prostate cancer, inhibits AR activity at low androgen levels, and even promotes degradation of the AR. The goal of this project is to understand which members of this network transmit the critical signals to the AR and how these signals modify known functions of the AR.

We will first dissect the signal transduction from the ErbB signaling network to the AR by genetic silencing or overexpression of individual members of this network. We will then examine how ErbB-mediated signals modify the assembly of the AR transcription complex on gene-regulatory regions of AR-regulated genes. Finally, we will examine how ErbB-mediated signals affect the stability of the AR protein. We expect that these studies will provide us with novel insights into the AR biology and guide the rational use of available inhibitors targeting the ErbB signaling network in prostate cancer.