Androgen receptor amplification is associated with increased cell proliferation in prostate cancer

• Published in: Human pathology Vol. 38; no. 3; pp. 474 - 478
• Main Authors: Haapala, Kyllikki, MSc, Kuukasjärvi, Tuula, MD, PhD, Hyytinen, Eija, PhD, Rantala, Immo, PhD, Helin, Heikki J., MD, PhD, Koivisto, Pasi A., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-03-2007; Elsevier; Elsevier Limited
• Subjects: Androgen Antagonists - therapeutic use; Androgen receptor; Androgens; Biological and medical sciences; Cell Proliferation; Flow cytometry; Gene Amplification; Gonadotropin-Releasing Hormone - antagonists & inhibitors; Hormonal therapy; Humans; Investigative techniques, diagnostic techniques (general aspects); Ki-67 Antigen - metabolism; Male; Medical sciences; Neoplasm Recurrence, Local; Nephrology. Urinary tract diseases; Orchiectomy; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Prostatic Neoplasms/genetics/metabolism/pathology/therapy; Receptors, Androgen - biosynthesis; Receptors, Androgen - genetics; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Cell proliferation; Gene amplification; Prostate cancer; Androgen receptor; Hormonal therapy; Urinary system disease; Prostate disease; Hormone therapy; Malignant tumor; Anatomic pathology; Association; Male genital diseases; Tumor cell; Hormonal receptor; Local; Receptors; Androgen/biosynthesis/genetics; Neoplasm Recurrence
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2006.09.008

Summary Mechanisms of prostate cancer progression during hormonal therapy and the pathobiologic consequences of androgen receptor ( AR ) gene amplification are inadequately known. To further investigate the hypothesis that AR gene amplification is associated with increased cell proliferation, we analyzed 123 paraffin-embedded prostate cancer specimens from men who experienced tumor relapse during androgen withdrawal therapy. We used fluorescence in situ hybridization to quantify AR gene copy number and Ki-67 immunohistochemistry to determine cell proliferation. One third of the tumors showed AR gene amplification. Among tumors with AR amplification, the mean cell proliferation rate was 19.8 (SD, 12.3; 95% confidence interval [CI], 15.4-24.1), whereas it was 13.0 (SD, 15.9; 95% CI, 9.1-16.8) in tumors without amplification ( P = .032). In the best fitting logistic regression model, only proliferation remained significant ( P = .040). When the median Ki-67 labeling index (6.7%) of all tumors was used as a cutoff point, the tumors with AR amplification were more frequently highly proliferating than tumors with no amplification ( P = .010; odds ratio, 3.4; 95% CI, 1.4-8.3). Our results imply that progression of prostate cancer during androgen withdrawal therapy is associated with AR gene amplification and increased cell proliferation rate in one third of tumors. We suggest that AR gene amplification is an important molecular mechanism underlying the increase in proliferation rate of a substantial fraction of recurrent prostate carcinomas. However, efforts should be targeted to develop prostate cancer cell lines to study causal relationships between AR gene amplification and various biologic variables.