Humanizing the Mouse Androgen Receptor to Study Polymorphisms and Mutations in Prostate Cancer.

摘要

Androgen receptor (AR) plays a critical role in prostate oncogenesis Allelic variants of AR, particularly in length of an N-terminal glutamine (Q) tract, are associated with distinct risks of disease. Mutation of AR in tumors may enter into resistance to treatment and androgen independence. Initiation and progression have been difficult to study due to lack of early disease samples and lack of animal models. This has been partly overcome with transgenic mouse tumor models However, mouse AR differs significantly from human in the N- terminus. In order to critically evaluate the role of the polymorphic glutamine tract in disease, and to identify relevant sites in the N-terminus whose mutation can lead to androgen-independent AR function, we have humanized the mouse by converting its androgen receptor gene to the human sequence. We have done this by homologous recombination in embryonic stem cells, introducing AR alleles with 12, 21, or 41 glutamines. Mice bearing the wild type allele with 21 glutamines are normal by all indications, including microarray analysis. However, expression of specific androgen target genes suggests subtle distinctions exist. This will be explored in detail by examining tumor progression and by sequencing AR cDNAs from tumors of castrated vs intact mice.