Progression to
hormone-refractory growth of
prostate cancer has been suggested to be mediated by
androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate
carcinomas treated with
orchiectomy,
estrogens, or a combination of
orchiectomy and
estramustine phosphate using fluorescence in situ hybridization, single-strand conformation polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16 (25%) and
amino acid changing mutations was observed in 7 of 21 (33%) of the
tumors, respectively. Two (50%)
tumors with AR amplification also had missense mutation of the gene. Four of five (80%)
cancers that were treated with a combination of
orchiectomy and
estramustine phosphate had a mutation clustered at
codons 514 to 533 in the N-terminal domain of AR. In functional studies, these mutations did not render AR more sensitive to
testosterone,
dihydrotestosterone,
androstenedione, or beta-
estradiol.
Tumors treated by
orchiectomy had mutations predominantly in the
ligand-binding domain. In summary, we found molecular alterations of AR in more than half of the prostate
carcinomas that recurred locally. Some
tumors developed both aberrations, possibly enhancing the
cancer cell to respond efficiently to low levels of
androgens. Furthermore, localization of point mutations in AR seems to be influenced by the type of treatment.