Gaddipati J P, McLeod D G, Heidenberg H B, Sesterhenn I A, Finger M J, Moul J W, Srivastava S
Urology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001.
Cancer Res. 1994 Jun 1;54(11):2861-4.
Prostatic tissue specimens derived from transurethral resections of patients with metastatic prostate cancer were analyzed for genetic alterations in the hormone-binding domain of the androgen receptor (AR) gene. Direct sequencing of the polymerase chain reaction-derived DNAs of 6 of 24 specimens revealed a codon 877 mutation (ACT-->GCT, Thr-->Ala) in the hormone-binding domain of the AR gene. This same AR mutation has been reported previously in a metastatic prostate cancer cell line, LNCaP, where this mutation confers upon the AR an altered ligand-binding specificity which is stimulated by estrogens, progestagens, and antiandrogens. It is possible that analogous to an activated/altered growth factor receptor oncogene, codon 877 mutant AR with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer. Although estrogens are used infrequently, antiandrogens are used increasingly in hormonal therapy for patients with advanced prostate cancer. The stimulatory effect of these therapeutic agents on the codon 877 mutant AR further suggests that this frequently observed AR mutation may contribute to the treatment refractory disease.
对转移性前列腺癌患者经尿道切除术获取的前列腺组织标本进行分析，以检测雄激素受体（AR）基因激素结合域的基因改变。对24个标本中的6个进行聚合酶链反应衍生DNA的直接测序，结果显示AR基因激素结合域存在密码子877突变（ACT→GCT，苏氨酸→丙氨酸）。此前在转移性前列腺癌细胞系LNCaP中也报道过相同的AR突变，该突变使AR具有改变的配体结合特异性，雌激素、孕激素和抗雄激素可刺激这种特异性。与激活/改变的生长因子受体癌基因类似，具有改变的配体结合能力的密码子877突变型AR可能在一部分晚期前列腺癌的发生过程中提供选择性生长优势。虽然雌激素很少使用，但抗雄激素在晚期前列腺癌患者的激素治疗中使用越来越多。这些治疗药物对密码子877突变型AR的刺激作用进一步表明，这种常见的AR突变可能导致治疗难治性疾病。
