Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy.
OBJECTIVE
Bcl-2 inhibits apoptosis, and its overexpression is associated with hormone refractory prostate cancer (HRPC). Bak and Bax are in the Bcl-2 family and counteract the antiapoptotic function of Bcl-2. Taxane-induced (paclitaxel and its analogue docetaxel) phosphorylation of Bcl-2 abolishes the potential antiapoptotic effect of Bcl-2. We hypothesized that (a) survival benefit in HRPC patients treated with taxanes is determined by the presence of Bcl-2 protein and (b) altered expression of Bak and Bax protein caused by genetic mutation is associated with biological aggressiveness of prostate cancer.


METHODS
Forty localized prostate cancer and 30 HRPC cases were used in this study. Surgical specimens of localized prostate cancer and biopsy specimens of HRPC were used for immunostaining of Bcl-2, Bak, and Bax as well as DNA extraction. Mutations in the Bak and Bax genes were screened by single-strand conformational polymorphism, and confirmed by direct DNA sequencing.


RESULTS
Bcl-2-positive HRPC showed longer cause-specific survival in comparison with the counterparts. Multivariate analysis revealed that the level of Bcl-2 expression before treatment with taxane-based chemotherapy was an independent predictor for cause-specific survival (P < 0.01) and baseline prostate-specific antigen level was an independent predictor for progression-free survival (P < 0.01). Bax gene mutation was found in only one HRPC specimen.


CONCLUSIONS
Bcl-2 expression in addition to prostate-specific antigen measurement before treatment could identify HRPC patients who may benefit from taxane-based chemotherapy. Mutation of the Bak and Bax genes is a rare event in prostate cancer.
Yoshino
Tateki
T
Department of Urology, Shimane University School of Medicine, Izumo, Japan.
Shiina
Hiroaki
H
Urakami
Shinji
S
Kikuno
Nobuyuki
N
Yoneda
Tatsuaki
T
Shigeno
Kazushi
K
Igawa
Mikio
M
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000469:parasitology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D043823:Taxoids / Q000627:therapeutic use*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein