The androgen-signaling pathway is important for the growth and progression of prostate cancer. Androgen ablation therapy, which may result in programmed cell death, is often used to treat advanced prostate cancer. The growth-promoting effects of androgen are mediated mostly through the androgen morphogenic proteins (BMPs), play critical roles in controlling prostate cell proliferation, differentiation, and apoptosis. The TGF-beta pathway is often inactivated by loss of normal transcripts and proteins of TGF-beta receptors in prostate cancer cells, especially in advanced stages of the disease. Since androgen promotes the growth and proliferation of prostatic epithelial cells and TGF-beta negatively regulates this process, a potential crosstalk between TGF-beta and androgen pathways has been proposed. However, to date there has been no data showing a direct link between these two important pathways, Recently, we demonstrated for the first time that Smad 3, a nuclear transducer of TGF-beta, specifically repressed transcriptional activation mediated by AR. This repression is transmitted directly through TGF- beta signaling and can be regulated by other Smad proteins. A protein- protein interaction between AR and Smad3 was identified both in vitro and in vivo. These results suggest that TGF-beta suppression of prostate cancer cell growth may be mediated through interaction with the androgen signaling pathway, and that the interaction between AR and Smad3 may be a convergent point between these two pathways. It is also possible that loss of TGF-beta signaling during the progression to androgen-independent disease may augment AR activity in the setting of decreased androgen. Our major objective in this proposal is to study the interaction between AR and Smad3 in order to understand the crosstalk between androgen and TGF-beta pathways in prostate cancer development and progression. Ultimately, we wish to determine the biological roles of Smad3 in cooperatively regulating AR functions (Aims 1 and 2) to determine whether expression of Smad3 is altered during prostate cancer progression (Aim 3). The long-term goal of this study is to identify new steps that can be targeted in the treatment of prostate cancer.
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