title: Androgen receptor amplification is associated with increased cell proliferation in prostate cancer.
abstract: 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.
authors.affiliation: Laboratory of Molecular Genetics, Centre for Laboratory Medicine, Tampere University Hospital, 33521 Tampere, Finland.
authors.forename: Kyllikki
authors.initials: K
authors.lastname: Haapala
authors.forename: Tuula
authors.initials: T
authors.lastname: Kuukasjärvi
authors.forename: Eija
authors.initials: E
authors.lastname: Hyytinen
authors.forename: Immo
authors.initials: I
authors.lastname: Rantala
authors.forename: Heikki J
authors.initials: HJ
authors.lastname: Helin
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Koivisto
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D049109:Cell Proliferation; D005784:Gene Amplification; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D009364:Neoplasm Recurrence, Local; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000726:Androgen Antagonists; D019394:Ki-67 Antigen; D011944:Receptors, Androgen; D007987:Gonadotropin-Releasing Hormone