Nearly 20 different transcripts of the human
androgen receptor (AR) are reported with two currently listed as Refseq
isoforms in the NCBI database.
Isoform 1 encodes wild-type AR (type 1 AR) and
isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2-8 but differ in exon 1 with the canonical exon 1 in
isoform 1 and the variant exon 1b in
isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b. Moreover, we identified AR transcripts in both normal and cancerous breast and prostate cells that contained either exon 1b or 1b/TAG spliced between the canonical exon 1 and exon 2, generating nine-exon AR transcripts that we have named
isoforms 3a and 3b. The
proteins encoded by these new AR variants could regulate
androgen-responsive reporters in breast and
prostate cancer cells under
androgen-depleted conditions. Analysis of type 3 AR-GFP fusion
proteins showed partial nuclear localization in PC3 cells under
androgen-depleted conditions, supporting
androgen-independent activation of the AR. Type 3 AR
proteins inhibited
androgen-induced growth of LNCaP cells. Microarray analysis identified a small set of type 3a AR target genes in LNCaP cells, including genes known to modulate growth and proliferation of
prostate cancer (PCGEM1, PEG3, EPHA3, and EFNB2) or other types of human
cancers (TOX3, ST8SIA4, and SLITRK3), and genes that are diagnostic/prognostic
biomarkers of
prostate cancer (GRINA3, and BCHE).