Isoform specific activities of androgen receptor and its splice variants in prostate cancer cells

Androgen receptor (AR) signaling continues to drive castration resistant
prostate cancer (CRPC) in spite of androgen deprivation therapy (ADT).
Constitutively active shorter variants of AR, lacking the ligand binding
domain, are frequently expressed in CRPC and have emerged as a potential
mechanism for prostate cancer to escape ADT.  ARv7 and ARv567es
are two of the most commonly detected variants of AR in clinical samples
of advanced, metastatic prostate cancer. It is not clear if variants of AR
merely act as weaker substitutes for AR or can mediate unique isoform
specific activities different from AR. In this study, we employed LNCaP
prostate cancer cell lines with inducible expression of ARv7 or ARv567es
to delineate similarities and differences in transcriptomics, metabolomics
and lipidomics resulting from the activation of AR, ARv7 or ARv567es.
While the majority of target genes were similarly regulated by the action
of all three isoforms, we found a clear difference in transcriptomic
activities of AR versus the variants, and a few differences between ARv7
and ARv567es. Some of the target gene regulation by AR isoforms was
similar in the VCaP background as well. Differences in downstream
activities of AR isoforms were also evident from comparison of the
metabolome and lipidome in an LNCaP model. Overall our study implies that
shorter variants of AR are capable of mediating unique downstream
activities different from AR and some of these are isoform specific.