ErbB3 in the development of androgen-independent prostate cancer

The ErbB family of receptor tyrosine kinases plays an important role in normal physiological processes during development and their deregulated expression has been implicated in multiple human cancers including prostate cancer. Prostate cancer cells initially depend on androgens for growth and survival, and are therefore responsive to androgen ablation. However, these tumors ultimately progress to androgen independent prostate cancer (AIPC), for which there is currently no established cure. The mechanism by which androgen dependent prostate cancer (ADPC) cells progress to AIPC remains largely unclear. The topic of this thesis is to determine whether ErbB3, a member of the ErbB family, plays a role in this progression, whether androgen ablation promotes ErbB3 overexpression and how this process can be prevented.;Secondly, we investigated the mechanism by which ErbB3 is upregulated in the development of AIPC. We made the novel observation that AR is a negative regulator of ErbB3 expression in ADPC cells, more importantly, the regulation of ErbB3 by the AR is post-transcriptional, and is mediated by Nrdp1, an E3 ubiquition ligase, whose role in prostate cancer has not previously been reported. An androgen response element (ARE) was found in the 5'-flanking region of Nrdp1. Our study showed that the androgen receptor can regulate Nrdp1 transcriptionally and in turn Nrdp1 negatively regulates the ErbB3 receptor expression in ADPC cells, but this regulation is lost in AIPC cells, therefore AIPC retains high ErbB3 levels, and causing increased proliferation.;To date, there is no ErbB3 receptor inhibitor that is commercially available. We therefore used an innovative method to inhibit ErbB3. Since ErbB4 is lost in prostate cancer (See Chapter I, 4.3.1), ErbB3 activation needs its dimerization with EGFR and ErbB2 in prostate cancer cells. Therefore we used dual EGFR and ErbB2 inhibition to prevent EGFR-ErbB3 and ErbB2-ErbB3 dimerization. Our data showed that simultaneous inhibition of EGFR and ErbB2 can block activation of ErbB3 and its downstream target, the PI3K/AKT pathway. Dual inhibition of EGFR and ErbB2 was more effective in reducing growth in prostate cancer cells, compared to individual inhibitors. Additional treatment with the AR antagonist bicalutamide, in combination with dual inhibition of EGFR and ErbB2, induced cell death. We show for the first time that the use of dual EGFR/ErbB2 inhibitors at the time of androgen ablation may prevent AIPC by inducing apoptosis in pre-AIPC cells.;In summary, this work indicates that ErbB3 overexpression is an early event in the development of AIPC following androgen ablation therapy. Therefore, ErbB3 may be a good therapy target at the time of androgen ablation therapy to prevent the onset of AIPC.;In this work androgen dependent LNCaP prostate cancer cells and its AI subline LNCaP-AI were used as models for ADPC and AIPC respectively. Firstly, we show for the first time that the overexpression of ErbB3 leads to higher AR transcriptional activity and provides cells with the ability to grow in low-androgen medium. In addition, increased ErbB3 expression also results in higher cell invasion rate. Our data demonstrate an important role for ErbB3 in the development and progression of prostate cancer.