title: Chemical castration and anti-androgens induce differential gene expression in prostate cancer.
abstract: Endocrine therapy by castration or anti-androgens is the gold standard treatment for advanced prostate cancer. Although it has been used for decades, the molecular consequences of androgen deprivation are incompletely known and biomarkers of its resistance are lacking. In this study, we studied the molecular mechanisms of hormonal therapy by comparing the effect of bicalutamide (anti-androgen), goserelin (GnRH agonist) and no therapy, followed by radical prostatectomy. For this purpose, 28 men were randomly assigned to treatment groups. Freshly frozen specimens were used for gene expression profiling for all known protein-coding genes. An in silico Bayesian modelling tool was used to assess cancer-specific gene expression from heterogeneous tissue specimens. The expression of 128 genes was > two-fold reduced by the treatments. Only 16% of the altered genes were common in both treatment groups. Of the 128 genes, only 24 were directly androgen-regulated genes, according to re-analysis of previous data on gene expression, androgen receptor-binding sites and histone modifications in prostate cancer cell line models. The tumours containing TMPRSS2-ERG fusion showed higher gene expression of genes related to proliferation compared to the fusion-negative tumours in untreated cases. Interestingly, endocrine therapy reduced the expression of one-half of these genes and thus diminished the differences between the fusion-positive and -negative samples. This study reports the significantly different effects of an anti-androgen and a GnRH agonist on gene expression in prostate cancer cells. TMPRSS2-ERG fusion seems to bring many proliferation-related genes under androgen regulation.
authors.affiliation: Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Lehmusvaara
authors.forename: Timo
authors.initials: T
authors.lastname: Erkkilä
authors.forename: Alfonso
authors.initials: A
authors.lastname: Urbanucci
authors.forename: Kati
authors.initials: K
authors.lastname: Waltering
authors.forename: Janne
authors.initials: J
authors.lastname: Seppälä
authors.forename: Antti
authors.initials: A
authors.lastname: Larjo
authors.forename: Vilppu J
authors.initials: VJ
authors.lastname: Tuominen
authors.forename: Jorma
authors.initials: J
authors.lastname: Isola
authors.forename: Paula
authors.initials: P
authors.lastname: Kujala
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
authors.forename: Antti
authors.initials: A
authors.lastname: Kaipia
authors.forename: Teuvo Lj
authors.initials: TLj
authors.lastname: Tammela
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
mesh_terms: D000284:Administration, Oral; D000704:Analysis of Variance; D000726:Androgen Antagonists / Q000008:administration & dosage*; D000813:Anilides / Q000008:administration & dosage*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D001499:Bayes Theorem; D002369:Castration / Q000379:methods*; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D005387:Finland; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000378:metabolism; D017273:Goserelin / Q000008:administration & dosage*; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D020360:Neoadjuvant Therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D009570:Nitriles / Q000008:administration & dosage*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D014105:Tosyl Compounds / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D014105:Tosyl Compounds; D017273:Goserelin; D007987:Gonadotropin-Releasing Hormone; C053541:bicalutamide