The AR gene maps to the X chromosome, thus rendering all mutations dominant in prostate cancer. Germ-line inactivating mutations of AR are well documented in the androgen-insensitivity syndrome.6,38
Similar to AR amplification, the frequency of AR mutations is rare in untreated prostate cancer. In contrast, AR mutations have been detected in as high as 50% of advanced and metastatic tumors, indicating that mutations are much more common in AI cancers.39,40 These mutations may be present from the onset of the cancer (but remain undetectable due to the low sensitivity of the available assays) or may be acquired. In either case, it appears that these mutations gain prominence under the selective pressure of androgen-ablative therapy, as seen with AR amplification.
Evidence for AR mutations in prostate cancer first surfaced when AR was studied in the metastatic prostate cancer cell line LNCaP. Sequencing results uncovered a single missense point mutation in codon 877 of AR, resulting in a threonine-to-alanine substitution (T877A).41,42 This mutation is located in the ligand-binding site of AR, and functional studies have revealed a change in the ligand-binding properties of the mutant AR. This mutation allows AR to bind to androgens, estrogens, progestagens, adrenal androgens, as well as many antiandrogens.43
This lack of specificity may also explain the flutamide withdrawal syndrome, in which patients show clinical deterioration with rising serum PSA levels while on the AR antagonist flu-tamide but then improve when the drug is removed. In other words, the antagonist behaves as an agonist. Taplin et al.40 showed the presence of the T877A mutation in 5/16 patients with bone metastases while on flutamide. However, this mutation is not unique as several other mutations, e.g., T877S, are able to convert flu-tamide to an agonist as well. Functional analysis revealed strong stimulation of these mutant ARs by flutamide. Interestingly, these mutants were inhibited by bicalutamide (Casodex), a related nonsteroidal AR antagonist. Since the initial publications, numerous mutations of AR have been discovered (e.g., V715M, V730M, H874Y, and L701H).44 Functional characterization of many of these mutants is in progress, and an updated list can be accessed at the Androgen Receptor Mutations Database (www.mcgill.ca/ androgendb). Mutations of AR (including T877A) have been found in cell lines from patients not previously treated with flutamide (i.e., LNCaP and CRW22).40 These AR mutants may allow prostate cancer cells to escape decreased androgen levels as well as conferring them with other as yet uncharacterized survival mechanisms. While neither AR amplification or AR mutations are likely to account for the majority of AI prostate cancers, they do illustrate the central role of altered AR function in late-stage disease.
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