title: Estrogen receptor β expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naive prostate cancer and are elevated in castration-resistant disease.
abstract: Patients with advanced prostate cancer (PC) are usually treated with androgen withdrawal. While this therapy is initially effective, nearly all PCs become refractory to it. As hormone receptors play a crucial role in this process, we constructed a tissue microarray consisting of PC samples from 107 hormone-naïve (HN) and 101 castration-resistant (CR) PC patients and analyzed the androgen receptor (AR) gene copy number and the protein expression profiles of AR, Serin210-phosphorylated AR (pAR(210)), estrogen receptor (ER)β, ERα and the proliferation marker Ki67. The amplification of the AR gene was virtually restricted to CR PC and was significantly associated with increased AR protein expression (P<0.0001) and higher tumor cell proliferation (P=0.001). Strong AR expression was observed in a subgroup of HN PC patients with an adverse prognosis. In contrast, the absence of AR expression in CR PC was significantly associated with a poor overall survival. While pAR(210) was predominantly found in CR PC patients (P<0.0001), pAR(210) positivity was observed in a subgroup of HN PC patients with a poor survival (P<0.05). Epithelial ERα expression was restricted to CR PC cells (9%). ERβ protein expression was found in 38% of both HN and CR PCs, but was elevated in matched CR PC specimens. Similar to pAR(210), the presence of ERβ in HN patients was significantly associated with an adverse prognosis (P<0.005). Our results strongly suggest a major role for pAR(210) and ERβ in HN PC. The expression of these markers might be directly involved in CR tumor growth.
authors.affiliation: Department of Urology, St Claraspital, Basel, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Zellweger
authors.forename: Susanne
authors.initials: S
authors.lastname: Stürm
authors.forename: Silvia
authors.initials: S
authors.lastname: Rey
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.forename: Joel R
authors.initials: JR
authors.lastname: Gsponer
authors.forename: Cyrill A
authors.initials: CA
authors.lastname: Rentsch
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Terracciano
authors.forename: Alexander
authors.initials: A
authors.lastname: Bachmann
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.forename: Christian
authors.initials: C
authors.lastname: Ruiz
mesh_terms: D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: C410798:AR protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011944:Receptors, Androgen
keywords: androgen receptor; castration resistance; estrogen receptor; hormone naïve; hormone receptors; prostate cancer