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Crosstalk Between The Androgen Receptor And β-Catenin In Castrate-Resistant Prostate Cancer

July 28, 2017

UroToday - The development of therapeutics for castration resistant prostate cancer depends on understanding the mechanism(s) involved in hormonal progression. The androgen receptor is a transcription factor that is important in the development of both the prostate and prostate cancer. The androgen receptor has also been found to be the only consistently changed factor in castration resistant disease. Therefore, it has been proposed to be the key factor in the mechanism of hormonal progression of prostate cancer. However, there was a lack of genomic evidence for the reactivation of the androgen receptor in this terminal stage of the disease until now. Through analyzing the global expression profiles of androgen-regulated genes using in vivo samples from castrated hosts, we confirmed the reactivation (at least partially) of the androgen receptor in castration resistant disease.

One potential mechanism for activation of the androgen receptor after androgen ablation therapy may involve interactions with the androgen receptor and its coregulators, such as β-catenin, in response to alternative signal transduction pathways. Changes in expression of the members of Wnt/β-catenin pathways suggested that more β-catenin protein would be available to be recruited by androgen receptor in the castration resistant stage. This was confirmed by co-localization and coimmunoprecipitation of endogenous β-catenin and androgen receptor using in vivo samples. Curiously no interaction between androgen receptor and β-catenin was detected in vivo in xenografts harvested from intact mice before androgen ablation in spite of reports from in vitro studies that this interaction is dependent upon androgen. Instead interaction between β-catenin and androgen receptor was only detected in castration resistant xenografts. These data are the first to show in vivo interaction between the androgen receptor and β-catenin.

Based upon the gene expression data obtained from samples during in vivo progression to castration resistant disease, a working model for a potential mechanism of how androgen receptor could be reactivated during hormonal progression of prostate cancer is proposed. Based on the mechanism of crosstalk between these two pathways, therapeutic intervention to block activation of the androgen receptor through interaction with the β-catenin pathway may be considered through:

1) knockdown of expression of β-catenin;

2) small molecules, or forced expression of high concentrations of competitive peptides, that inhibit the phosphorylation of β-catenin thereby resulting in its degradation;

3) expression of high concentrations of the interaction motifs of these two proteins to competitively block their interaction; or

4) small molecules which can block the interaction between AR and β-catenin.

However, potential reactivation of the androgen receptor through interaction with β-catenin may not be involved in all cases of advanced disease and rather may pertain to only a subset of patients. Multi-level approaches of reducing levels of androgen and blocking androgen receptor activity through combinations of androgen ablation, antiandrogens or knockdown of androgen receptor, and blocking the interaction between androgen receptor and its co-regulators such β-catenin may provide a more complete and sustained blockade of androgen receptor activity for patients with advanced prostate cancer.

Marianne D Sadar, PhD as part of Beyond the Abstract on UroToday

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