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Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases

Kallio, Heini M.L.; Hieta, Reija; Latonen, Leena; Brofeldt, Anniina; Annala, Matti; Kivinummi, Kati; Tammela, Teuvo L.; Nykter, Matti; Isaacs, William B. and Lilja, Hans G. LU , et al. (2018) In British Journal of Cancer 119(3). p.347-356
Abstract

Background: A significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC. Methods: We analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry. Results: AR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they... (More)

Background: A significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC. Methods: We analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry. Results: AR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they were not associated with expression of previously known AR-Vs. The predominant AR-Vs detected were AR-V3, AR-V7 and AR-V9, with the expression levels being significantly higher in CRPC cases compared to prostatectomy samples. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs. AR-V7 protein expression was highly heterogeneous and higher in CRPC compared to hormone-naïve tumours. Conclusions: AR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC.

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publication status
published
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British Journal of Cancer
volume
119
issue
3
pages
347 - 356
publisher
Nature Publishing Group
external identifiers
  • scopus:85049612309
ISSN
0007-0920
DOI
10.1038/s41416-018-0172-0
language
English
LU publication?
yes
id
312a56a2-e0a0-476b-ac52-e2d0eed3d461
date added to LUP
2018-07-20 10:52:28
date last changed
2019-01-14 15:33:32
@article{312a56a2-e0a0-476b-ac52-e2d0eed3d461,
  abstract     = {<p>Background: A significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC. Methods: We analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry. Results: AR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they were not associated with expression of previously known AR-Vs. The predominant AR-Vs detected were AR-V3, AR-V7 and AR-V9, with the expression levels being significantly higher in CRPC cases compared to prostatectomy samples. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs. AR-V7 protein expression was highly heterogeneous and higher in CRPC compared to hormone-naïve tumours. Conclusions: AR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC.</p>},
  author       = {Kallio, Heini M.L. and Hieta, Reija and Latonen, Leena and Brofeldt, Anniina and Annala, Matti and Kivinummi, Kati and Tammela, Teuvo L. and Nykter, Matti and Isaacs, William B. and Lilja, Hans G. and Bova, G. Steven and Visakorpi, Tapio},
  issn         = {0007-0920},
  language     = {eng},
  month        = {07},
  number       = {3},
  pages        = {347--356},
  publisher    = {Nature Publishing Group},
  series       = {British Journal of Cancer},
  title        = {Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases},
  url          = {http://dx.doi.org/10.1038/s41416-018-0172-0},
  volume       = {119},
  year         = {2018},
}