SIRNA-directed in vivo silencing of androgen receptor inhibits the growth of castration-resistant prostate carcinomas.
BACKGROUND
Prostate carcinomas are initially dependent on androgens, and castration or androgen antagonists inhibit their growth. After some time though, tumors become resistant and recur with a poor prognosis. The majority of resistant tumors still expresses a functional androgen receptor (AR), frequently amplified or mutated.


RESULTS
To test the hypothesis that AR is not only expressed, but is still a key therapeutic target in advanced carcinomas, we injected siRNA targeting AR into mice bearing exponentially growing castration-resistant tumors. Quantification of siRNA into tumors and mouse tissues demonstrated their efficient uptake. This uptake silenced AR in the prostate, testes and tumors. AR silencing in tumors strongly inhibited their growth, and importantly, also markedly repressed the VEGF production and angiogenesis.


CONCLUSIONS
Our results demonstrate that carcinomas resistant to hormonal manipulations still depend on the expression of the androgen receptor for their development in vivo. The siRNA-directed silencing of AR, which allows targeting overexpressed as well as mutated isoforms, triggers a strong antitumoral and antiangiogenic effect. siRNA-directed silencing of this key gene in advanced and resistant prostate tumors opens promising new therapeutic perspectives and tools.
Compagno
Daniel
D
CNRS, University Paris-Sud, FRE2944, Epigenetics and Cancer, Institut André Lwoff, Villejuif, France.
Merle
Carole
C
Morin
Aurélie
A
Gilbert
Cristèle
C
Mathieu
Jacques R R
JR
Bozec
Aline
A
Mauduit
Claire
C
Benahmed
Mohammed
M
Cabon
Florence
F
D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics*; D013737:Testis / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D042461:Vascular Endothelial Growth Factor A