ANDROGEN RECEPTOR GENE MUTATION IN MALE BREAST-CANCER

We screened thirteen male breast cancers for the presence of germline mutations in exons 2 and 3 encoding the DNA-binding domain of the andr ogen receptor. These two exons were amplified from genomic DNA extract ed from patients' white blood cells. In one of these thirteen patients , single strand conformation polymorphism and direct sequencing detect ed a guanine-adenine point mutation at nucleotide 2185 that changes Ar g608 into Lys in a highly conserved region of the second zinc finger o f the androgen receptor. This mutation occurred in a 38 year old man w ith partial androgen insensitivity syndrome and normal androgen-bindin g capacity in cultured genital skin fibroblasts. To our knowledge, onl y one germline Arg to Gln androgen receptor gene mutation has been pre viously reported at position 607 in male breast cancer. This androgen receptor mutation along with the Arg608 into Lys mutation we describe, suggests that this genetic abnormality is not fortuitous: a decrease in androgen action within the breast cells could account for the devel opment of male breast cancer by the loss of a protective effect of and rogens on these cells. Activation of estrogen regulated genes by the c hange of DNA-binding characteristics of the mutant androgen receptor c annot, however, be ruled out.