Collocation of androgen receptor gene mutations in prostate cancer

Consistent with both the development of the normal prostate gland and prost ate tumorigenesis being dependent on testicular androgens, targeting the an drogen-signaling axis (i.e., androgen ablation therapy) remains the predomi nant treatment regime for patients with metastatic prostate cancer. Althoug h there is a very good initial response to androgen ablation, these treatme nts are essentially palliative, Recent evidence suggests that treatment fai lure may not result from a loss of androgen signaling but, rather, from the acquisition of genetic changes that lead to aberrant activation of the and rogen-signaling axis. A consistent finding is that androgen receptor (AR) g ene mutations, present in metastatic prostate cancer and in human prostate cancer cell lines as well as in xenograft and other animal models, result i n decreased specificity of ligand-binding and inappropriate receptor activa tion by estrogens, progestins, adrenal androgens, glucocorticoids and/or AR antagonists. Because a significant proportion of missense mutations in the AR gene reported in prostate cancer collocate to the signature sequence an d AF-2, two discrete regions of the ligand-binding domain critical for andr ogen signaling, we recently proposed that collocation of mutations identifi ed in prostate cancer would identify additional regions of the AR important in receptor function. This approach led to the identification of a four-am ino acid region at the boundary of the hinge and ligand-binding domains of the receptor that forms half of a potential protein-protein binding site. A R gene mutations have also been identified that collocate to areas in the D NA-binding domain, to the NH,-terminal transactivation domain, and to the h inge region in prostate tumors. In nearly every case, missense mutations in the AR gene identified in prostate cancer that collocate to discrete regio ns of the receptor contribute to altered androgen signaling and provide a p otential mechanism to explain the reemergence of tumor growth during the co urse of hormone ablation therapies.