Bcl-2 Expression as a Predictive Marker of Hormone-Refractory Prostate Cancer Treated with Taxane-Based Chemotherapy

• Published in: Clinical cancer research Vol. 12; no. 20; pp. 6116 - 6124
• Main Authors: YOSHINO, Tateki, SHIINA, Hiroaki, URAKAMI, Shinji, KIKUNO, Nobuyuki, YONEDA, Tatsuaki, SHIGENO, Kazushi, IGAWA, Mikio
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.10.2006
• Subjects: Aged; Antineoplastic agents; Antineoplastic Agents - therapeutic use; apoptosis; Bak; Bax; Bcl-2; bcl-2 Homologous Antagonist-Killer Protein - genetics; bcl-2-Associated X Protein - genetics; Biological and medical sciences; DNA, Neoplasm - genetics; Drug Resistance, Neoplasm; Exons - genetics; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; hormone refractory prostate cancer; Humans; Magnetic Resonance Spectroscopy; Male; Male genital diseases; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - parasitology; Proto-Oncogene Proteins c-bcl-2 - genetics; taxanes; Taxoids - therapeutic use; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Treatment resistance; Urinary system disease; Prostate disease; Hormone therapy; Biological marker; Malignant tumor; Gene expression; Chemotherapy; C-Onc gene; Taxane derivatives; Male genital diseases; Prostate cancer; Protooncogene
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0147

Purpose: 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. Experimental Design: 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.