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

摘要

Androgen receptor (AR) plays a critical role in prostate cancer. Length of AR's N-terminal glutamine (Q) tract has been associated with disease risk, and AR somatic mutation may influence disease progression. To study the basis for these effects in an animal model, we converted the mouse AR gene to the human sequence, using homologous recombination in embryonic stem cells. Mice bearing humanized AR alleles with 12, 21, or 48 Qs are normal in growth and fertility; subtle differences in some traits and gene expression were within normal biological variability. Differences are more apparent when crossed with TRAMP, providing a prostate oncogene. In intact mice, age at initiation is similar for wild type and 21Q hAR mice , but tumors in 12Q mice arise earlier and those in 48Q mice are significantly delayed. This corroborates epidemiological data showing inverse correlation of Q tract length with risk of disease. Remarkably, disease progression in castrated mice, mimicking androgen-independence, shows the opposite effect 12Q AR is strongly protective against onset of disease. The basis of this has been assessed histologically by tissue microarray, at the molecular level by sequencing AR cDNAs for mutations, and we are pursuing Q-tract effects on ligand-independent AR activation.