The polymorphic CAG repeat of the androgen receptor gene: a potential rolein breast cancer in women over 40

Previous investigations into the relationship of CAG-repeat lengths in the androgen receptor (AR) gene to female breast cancer (BC) have yielded somew hat confusing results. Decreased AR transactivational activity lowers andro gen:estrogen balance, and may thereby effect functional hyperestrogenicity. This may promote the pathogenesis of BC. To elucidate whether longer CAG r epeats of the AR gene (AR), which correlate with lower transactivational ac tivity of the AR, are associated with BC in women over 40, we examined the distribution of CAG-repeat lengths in BC tissue from this population. The B C tissue was histologically graded as: Grade 1, well differentiated (WD); G rade 2, moderately differentiated (MD); and Grade 3, poorly-differentiated (PD). Analysis showed significant differences as compared to controls when CAG lengths greater than 21 were examined, and that alleles with greater th an or equal to 26 repeats were 2.4-fold more frequent in BC samples than in constitutional samples from a normal population. A significant shift to gr eater CAG-repeat lengths, appeared in WD and MD tumors only. Our results gi ve some indication as to the progression of BC by suggesting that hypotrans active ARs with long polyglutamine (polyGln) tracts may have a role in the initiation and/or progression of BC. PD tumors tended to have shorter than normal CAG-repeat lengths. In this case it is hypothesized that the ARs hav e now become hypertransactive, possibly coinciding with the estrogen resist ance that is associated with PD tumors. Whether this shift is of germline o r somatic origin was not clear, though the appearance in 14% of the BC samp les of a third CAG-repeat length indicates that it may be somatic.