Title:Androgen Receptor and its Coactivators in Prostate Cancer: Novel Mechanisms for Androgen-Independent Disease

Presenter:Prof. Peng Lee, MD, PhD

University: Department of Pathology, Department of Urology, New York University School of Medicine

Time: 10:00-11:00, 25 April, 2011

Venue: A202, Institute of Microbiology, Chinese Academy of Sciences

Abstract:

A major obstacle in the treatment of prostate cancer is the development of androgen-independent disease. One of the underlying causes of androgen-independent disease is the up regulation of AR expression, however, the mechanism of AR gene regulation in androgen-independent cancer is not well understood.

We have recently shown that Lef1, a transcription factor activated by WNT signaling, induced expression of the AR gene in androgen-independent prostate cancer cell line, and consequently enhanced cell proliferation and invasion. This suggests that inhibition Lef1 by blocking WNT signaling may represent a new therapeutic approach in combating androgen-independent prostate cancer.

In addition to changes in AR expression, alterations in the level or splicing of AR coactivators could also contribute to androgen-independent prostate cancer cell proliferation. In fact, our lab has found that the AR coactivator ARA70α functions as a tumor suppressor gene in prostate cancer cells. Specifically, the interaction between AR and ARA70α leads to prostate cancer cell apoptosis. Interestingly, an AR mutation T877A, the receptor variant present in the LNCaP prostate cancer line, showed decreased interaction with ARA70α, which resulted in a reduced apoptosis and decreased growth inhibition of LNCaP cells. In contrast, a spliced form of ARA70, called ARA70β behaves as an oncogene, increasing prostate cancer growth and invasion. Interestingly, the proliferative effect of ARA70β is AR dependent, whereas enhancement of invasion is AR independent. We would therefore predict in tumors that express ARA70β, androgen ablation would cause cell growth arrest, but would not reduce the cells ability to invade.

While the majority of studies on AR focus on its action in epithelial cells, we are also examining the function of AR in prostate stromal cells. We have shown, using an epithelial-stromal cell coculture system, that AR expression in stromal cells inhibits prostate epithelial cell growth and invasion. We also found that androgen ablation prevented AR in the stroma from suppressing epithelial growth and invasion. Therefore, the lack of stromal AR signaling may, in turn, facilitate the survival, growth, and invasion of a sub-population of the epithelial prostate cancer cells, eventually leading to androgen-independence.

Taken together, our findings lend new insights into the development of androgen-independent prostate cancer and could lead to the development of novel therapies against the disease.