Conclusions

Herein, we describe the presence of two tumor cell clones harboring different AR mutations within the same hormone refractory metastatic PCA. These findings provide direct evidence for the clonal outgrowth of androgen-independent PCA cells with AR mutations in response to selective pressure from hormonal therapies. The coexistence oftumor clones expressing mutant ARs harboring either the T877A mutation or the Q640Stop/T877A double mutation argues that the event Q640Stop has occurred later during the disease history probably in response to a new selective pressure from one of the treatments that followed flutamide.

This study is the first report of a constitutively activated mutant AR in PCA and describes a new way by which PCA cells may escape androgen deprivation. In addition, this study demonstrates the great efficacy of our yeast functional assay for the detection of mutant ARs in PCA, and the analysis of their transactivation properties. By performing the assay on total RNA isolated from primary tumor samples, from hormone-sensitive metastases, and ultimately from hormone-resistant metastatic foci, we should be able to detect the clonal outgrowth of PCA cells with mutant AR during the disease evolution. Data obtained from these studies will provide a better understanding of the AR functions in the metastatic progression of the disease, and in the escape to androgen-dependent growth after androgen ablation therapies.

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