Tilley W D, Buchanan G, Hickey T E, Bentel J M
Cancer Cell Biology Laboratory, Department of Surgery, School of Medicine, Flinders University of South Australia, Bedford Park, SA 5042, Australia.
Clin Cancer Res. 1996 Feb;2(2):277-85.
Progression to androgen-independent growth of human prostate cancers may be mediated by alterations in the structure and/or expression of the androgen receptor (AR) gene. To date, mutations in the AR gene have largely been identified in hormone refractory tumors. In this study, single-strand conformational polymorphism analysis and DNA sequencing of the entire AR gene coding region was performed on 25 primary prostate tumors sampled prior to initiation of hormonal (i.e. , androgen ablation) therapy. Base changes leading to amino acid substitutions in the AR were identified in 11 (44%) tumors. The presence of AR amino acid substitutions was associated with decreased immunohistochemical staining for AR in tumor cells and the rapid failure of subsequent hormonal therapies. Single-strand conformational polymorphism analysis of exons 2, 3, and 8 of the X-linked hypoxanthine guanine phosphoribosyl transferase (HPRT) gene in the same samples revealed no bandshifts, suggesting that the high frequency of AR gene mutations detected was not a consequence of generalized genetic instability. These data indicate that AR gene mutations occur commonly in advanced prostate cancers prior to endocrine treatment of disease and may contribute to altered androgen responsiveness of the tumors.
人类前列腺癌向雄激素非依赖性生长的进展可能是由雄激素受体（AR）基因结构和/或表达的改变介导的。迄今为止，AR基因的突变主要在激素难治性肿瘤中被发现。在本研究中，对25例在激素（即雄激素去除）治疗开始前采集的原发性前列腺肿瘤进行了单链构象多态性分析和整个AR基因编码区的DNA测序。在11例（44%）肿瘤中鉴定出导致AR氨基酸替换的碱基变化。AR氨基酸替换的存在与肿瘤细胞中AR免疫组化染色减少以及随后激素治疗的快速失败相关。对相同样本中X连锁次黄嘌呤鸟嘌呤磷酸核糖基转移酶（HPRT）基因的第2、3和8外显子进行单链构象多态性分析，未发现条带移位，提示检测到的AR基因突变的高频率并非普遍遗传不稳定性的结果。这些数据表明，AR基因突变在晚期前列腺癌内分泌治疗前普遍存在，可能导致肿瘤雄激素反应性改变。
