Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient.
Androgen ablation therapies are effective in controlling prostate cancer. Although most cancers relapse and progress despite androgen ablation, some patients experience antiandrogen withdrawal syndrome, in which those treated with antiandrogen show clinical improvement when antiandrogen is discontinued. Although the androgen receptor (AR) is suggested to play an important role in prostate cancer progression even after the androgen ablation, limited tissue availability for molecular studies and small numbers of human prostate cancer cell lines have restricted prostate cancer research. Here, we describe KUCaP, a novel serially transplantable human prostate cancer xenograft model. We established KUCaP from liver metastatic tissue of a patient treated with antiandrogen bicalutamide. KUCaP expressed the AR with a point mutation at amino acid 741 (tryptophan to cysteine; W741C) in the ligand-binding domain. This mutation was also present in cancerous tissue used for generation of KUCaP. Although the growth of KUCaP in male mice was androgen dependent, bicalutamide aberrantly promoted the growth and prostate-specific antigen production of KUCaP. For the first time, we show the agonistic effect of bicalutamide to a xenograft with clinically induced AR mutation. This bicalutamide-responsive mutant AR will serve in the development of new therapies for androgen ablation-resistant prostate cancers.
Yoshida
Toru
T
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kinoshita
Hidefumi
H
Segawa
Takehiko
T
Nakamura
Eijiro
E
Inoue
Takahiro
T
Shimizu
Yousuke
Y
Kamoto
Toshiyuki
T
Ogawa
Osamu
O
D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D005091:Exons; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D009570:Nitriles; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics; D014105:Tosyl Compounds; D014183:Transplantation, Heterologous
D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide