Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22Rv1 hormone-refractory prostate cancer (PCa) cell line.
Advanced prostate cancer (PCa) has emerged as a public health concern due to population aging. Although androgen deprivation has proven efficacy in this condition, most advanced PCa patients will have to face failure of androgen deprivation as a treatment. Mutations in the androgen receptor (AR) from tumor cells have been shown to induce androgen independency both in PCa cell lines and in the clinic. We have investigated the molecular events leading to androgen independency in the 22Rv1 cell line, a commonly used preclinical model of PCa. Besides AR mutants that have been described so far, including nonsense mutations, recent data have focused on AR pre-mRNA aberrant splicing as a new mechanism leading to constitutively active truncated AR variants. In this article, we describe two novel variants arising from aberrant splicing of AR pre-mRNA, characterized by long mRNA transcripts that encode truncated, constitutively active proteins. We also describe several new nonsense mutants that share ligand independency and transcriptional activity. Finally, we show that alongside these mutants, 22Rv1 cells also express a mutant AR lacking exon 3 tandem duplication, a major feature of this cell line. By describing unreported AR mutants in the 22Rv1 cell line, our data emphasize the complexity and heterogeneity of molecular events that occur in preclinical models, and supposedly in the clinic. Future work on the 22Rv1 cell line should take into account the concomitant expression of various AR mutants.
Marcias
Gemma
G
Signalisation et Cancer de la Prostate, Physiopathologie et Médecine Translationnelle, Université de Strasbourg, 67000Strasbourg, France.
Erdmann
Eva
E
Lapouge
Gaëlle
G
Siebert
Christelle
C
Barthélémy
Philippe
P
Duclos
Brigitte
B
Bergerat
Jean-Pierre
JP
Céraline
Jocelyn
J
Kurtz
Jean-Emmanuel
JE
D017398:Alternative Splicing; D000728:Androgens / Q000378:metabolism; D045744:Cell Line, Tumor; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D008297:Male; D009154:Mutation; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism
C410798:AR protein, human; D000728:Androgens; D012322:RNA Precursors; D011944:Receptors, Androgen