MUTATED HUMAN ANDROGEN RECEPTOR GENE DETECTED IN A PROSTATIC-CANCER PATIENT IS ALSO ACTIVATED BY ESTRADIOL

Androgens are necessary for the development of prostatic cancer. The m echanisms by which the originally androgen-dependent prostatic cancer cells are relieved of the requirement to use androgen for their growth are largely unknown. The human prostatic cancer cell line LNCaP has b een shown to contain a point mutation in the human androgen receptor g ene (hAR), suggesting that changes in the hAR may contribute to the ab normal hormone response of prostatic cells. To search for point mutati ons in the hAR, we used single strand conformation polymorphism analys is and a polymerase chain reaction direct sequencing method to screen 23 prostatic cancer specimens from untreated patients, 6 prostatic can cer specimens From treated patients, and 11 benign prostatic hyperplas ia specimens. One mutation was identified in DNA isolated from prostat ic cancer tissue, and the mutation was also detected in the leukocyte DNA of the patient and his offspring. The mutation changed codon 726 i n exon E from arginine to leucine and was a germ line mutation. The mu tation we found in exon E of the hAR gene does not alter the ligand bi nding specificity of the AR, but the mutated receptor was activated by estradiol to a significantly greater extent than the wildtype recepto r. The AR gene mutation described in this study might be one explanati on for the altered biological activity of prostatic cancer.