Biological insights arising from the identification of genes and pathways that are regulated by the androgen receptor


Year:

Session type:

Ian Mills
University of Oslo, Norway & Cancer Research UK Cambridge Institute, UK

Abstract

Androgens contribute significantly to the development of localized prostate cancer and to progression. This is highlighted by the efficacy of abiraterone, an inhibitor of steroid hormone biosynthesis, in the treatment of advanced disease. The androgen receptor, a nuclear hormone receptor, is a principal mediator of the effects on androgens in prostate cancer. Considerable effort has been expended to define the genes and pathways that are regulated by the androgen receptor in prostate cancer. Clinical transcriptomic data reveal increased expression of genes associated with metabolic pathways, glycosylation and calcium signalling in localized disease. A cell cycle signature becomes apparent in advanced disease. Our work and the work of others indicate that the androgen receptor plays a key role in maintaining tumour cell metabolism and in addition, in advanced disease, in affecting the regulation of cell cycle checkpoints. Changes in the spectrum of androgen receptor binding sites and target genes/pathways reflect changes in androgen receptor expression but also in the cellular context in which it functions. Whilst current research has helped to identify interesting metabolic targets for drug development, future studies will require a yet more systematic dissection of the effects that tissue context and changes in cytokines and growth factors have on androgen receptor activity. This will require technical innovations to enable the sensitive and direct application of chromatin immunoprecipitation and genomic technologies to heterogeneous clinical samples.