Abstract
Androgen receptor (AR) variants are associated with resistance to anti androgen therapy both in human prostate cancer cell lines and clinical samples. These observations support the hypothesis that AR isoform accumulation is a consequence of selective therapeutic pressure on the full length AR. The Pten deficient prostate cancer model proceeds with well-defined kinetics including progression to castration resistant prostate cancer (CRPC). While surgical castration and enzalutamide treatments yield an initial therapeutic response, Pten-/-epithelia continue to proliferate yielding locally invasive primary tumor pathology. That most epithelium remains AR positive, but ligand independent, suggests the presence of oncogenic AR variants. To address this hypothesis, we have used a panel of recently described Pten-/- tumor cell lines derived from both from hormone intact (E4, E8) and castrated Pten mutants (cE1, cE2) followed by RACE PCR to identify and characterize three novel truncated, amino terminus containing AR variants (mAR-Va, b, c). Variants appear not only conserved throughout progression but are correlated with nearly complete loss of full length AR (AR-FL) at castrate androgen levels. The overexpression of variants leads to enhanced transcriptional activity of AR while knock down studies show reduced transcriptional output. Collectively, the identification of truncated AR variants in the conditional PTEN deletion model supports a role for maintaining the CRPC phenotype and provides further therapeutic applications of this preclinical model.
Highlights
Prostate cancer cells have been hypothesized to progress to castration resistance through a multitude of androgen receptor (AR) modifications including amplification, gene rearrangementsPLOS ONE | DOI:10.1371/journal.pone.0131232 July 21, 2015Androgen Receptor Variants in the Pten Null Prostate Cancer Model or mutations, altered expression of transcriptional co-regulators and de novo steroidogenesis [1,2,3,4,5,6]
The identification of AR variants in human castration resistant prostate cancer (CRPC) cell lines and clinical samples suggests that AR variants may facilitate continued AR oncogenic function despite the presence of AR targeted therapy [31]
This may be attributed to the fact that the majority of AR splice variants (AR-Vs) identified so far are predicted to encode proteins lacking the LBD but retaining the N-terminal transactivation domain thereby acting as the constitutively active transcription factors
Summary
Prostate cancer cells have been hypothesized to progress to castration resistance through a multitude of androgen receptor (AR) modifications including amplification, gene rearrangementsPLOS ONE | DOI:10.1371/journal.pone.0131232 July 21, 2015Androgen Receptor Variants in the Pten Null Prostate Cancer Model or mutations, altered expression of transcriptional co-regulators and de novo steroidogenesis [1,2,3,4,5,6]. Studies with human prostate cancer cell lines and tissues have identified the presence of AR splice variants (AR-Vs) which can be up-regulated in response to castration and promote resistance to androgen receptor targeted therapy [7,8,9] [10] [11]. To date up to 15 different AR-Vs lacking different portions of LBD have been reported in human prostate cancer cell lines CWR-R1, 22rv, VCaP and LuCaP xenografts [14,15,16,17,18,19,20,21]. AR isoforms remain vastly understudied in preclinical mouse models of prostate cancer tissues being limited to two AR-Vs as reported using the Myc-CaP cell line [15]. No AR variants have been reported from the primary organ of a preclinical mouse model of prostate cancer
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