Codon 877 Mutation in the Androgen Receptor Gene in Advanced Prostate Cancer: Relation to Antiandrogen Withdrawal Syndrome

Abstract

The growth of prostate cancer is androgen responsive, and androgen receptor (AR) is thought to play an important role in the development of this cancer. Recently, some reports demonstrated that AR gene mutations were detected in human prostate cancer tissues. We have previously reported that one of eight endocrine therapy‐resistant prostate cancer cases showed AR gene mutation [Suzuki] et al: J Steroid Biochem Mol Biol46:759‐76, 19931. To further investigate structural abnormality of the AR in a large number of human prostate cancers, exons E H encoding DNA‐ and hormone‐binding domains were examined by single‐strand conformation polymorphism analysis of polymerase chain reaction products and direct sequencing. Tissues surgically removed from 30 cases of stage B or C prostate cancer and from 22 cases of endocrine therapy‐resistant cancers obtained at autopsy were used in the study. Three out of 22 cancer death cases (14%) revealed AR gene mutations, one of which contained two different mutations‐exon D in cancerous prostate and exon H in metastatic tissues. In the other two cases, AR gene mutations in exon H were found in metastatic tissues. All three cases in metastatic tissues showed the same mutation at codon 877 (877Thr + Ala). In stage B or C cancer tissues and the other cancer death samples, no AR mutation was detected. The mutation in exon H was identical to that reported in a human prostate cancer cell line, LNCaP. These results indicate that AR gene mutation scarcely occurs in the early stage of prostate cancer and that the mutation is found in relation to endocrine therapy resistance. Two patients with an AR gene mutation at codon 877 revealed a remarkable fall in prostate‐specific antigen after withdrawal of antiandrogen. Data on the other case were not available. These results indicate that a codon 877 mutation in the AR gene in advanced prostate cancer evokes the antiandrogen withdrawal syndrome. To our knowledge, this report is the first description of relationship between an AR mutation at codon 877 and the antiandrogen withdrawal syndrome. © 1996 Wiley‐Liss, Inc.

Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer

“…To avoid this difficulty, we have introduced a modified Cre-loxP system to selectively introduce a point mutation into the AR LBD in the prostates of adult mice (AR pe-T877A/Y mice). This mutation (T877A) is often seen in prostatic tumors of androgenindependent patients (17,18).…”

“…As the hydrophobic pocket in the LBD specifically recognizes and captures androgens and AR ligands, the mutated amino acid residues in the LBD, particularly in the motifs constituting the pocket, are presumed to impair specificity in hormone/ligand recognition. Indeed, in in vitro cell cultures, such human (h)AR point mutants display acquired responsiveness to other steroid hormones and androgen antagonists (17,18). The point mutation threonine 877 to alanine (T877A) in the LBD is one of the most common mutations in prostate tumors (15,16).…”

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

“…In spite of the initial repressive effects, essentially all prostate cancers escape from antiandrogen therapy. In some of these hormone refractory tumours, a hot-spot AR mutation (Thr 877 → Ala; T877A) has been reported [12,13]. The mutation, which was initially detected in the prostate tumour cell line LNCaP [14], strongly affects AR steroid binding characteristics and its response to a variety of non-androgenic hormones and antiandrogens [14][15][16].…”

Expression and somatic mutation on androgen receptor gene in prostate cancer

“…13 However, in most of the studies, only a low frequency of mutations has been observed in the advanced-stage cancers or even in the hormone-refractory recurrent prostate cancers. 14,15 The association between the progression and AR expression or mutations of the AR gene is still not well defined. In the present study, we evaluated the prognostic significance of AR expression and AR gene mutations in 42 cases.…”