Lobaccaro J M, Lumbroso S, Belon C, Galtier-Dereure F, Bringer J, Lesimple T, Namer M, Cutuli B F, Pujol H, Sultan C
Institut National de la Santé et de la Recherche Médicale, INSERM U58, Montpellier, France.
Hum Mol Genet. 1993 Nov;2(11):1799-802. doi: 10.1093/hmg/2.11.1799.
We screened thirteen male breast cancers for the presence of germline mutations in exons 2 and 3 encoding the DNA-binding domain of the androgen receptor. These two exons were amplified from genomic DNA extracted from patients' white blood cells. In one of these thirteen patients, single strand conformation polymorphism and direct sequencing detected a guanine-adenine point mutation at nucleotide 2185 that changes Arg608 into Lys in a highly conserved region of the second zinc finger of the androgen receptor. This mutation occurred in a 38 year old man with partial androgen insensitivity syndrome and normal androgen-binding capacity in cultured genital skin fibroblasts. To our knowledge, only one germline Arg to Gln androgen receptor gene mutation has been previously reported at position 607 in male breast cancer. This androgen receptor mutation along with the Arg608 into Lys mutation we describe, suggests that this genetic abnormality is not fortuitous: a decrease in androgen action within the breast cells could account for the development of male breast cancer by the loss of a protective effect of androgens on these cells. Activation of estrogen regulated genes by the change of DNA-binding characteristics of the mutant androgen receptor cannot, however, be ruled out.
我们筛查了13例男性乳腺癌，以检测编码雄激素受体DNA结合域的外显子2和外显子3中是否存在种系突变。这两个外显子是从患者白细胞中提取的基因组DNA中扩增出来的。在这13例患者中的1例中，单链构象多态性和直接测序检测到核苷酸2185处的鸟嘌呤-腺嘌呤点突变，该突变在雄激素受体第二个锌指的高度保守区域将精氨酸608变为赖氨酸。此突变发生在一名38岁男性身上，该男性患有部分雄激素不敏感综合征，其培养的生殖器皮肤成纤维细胞中的雄激素结合能力正常。据我们所知，先前仅在男性乳腺癌的607位报道过1种种系精氨酸到谷氨酰胺的雄激素受体基因突变。我们描述的这种雄激素受体突变以及精氨酸608变为赖氨酸的突变表明，这种基因异常并非偶然：乳腺细胞内雄激素作用的降低可能是由于雄激素对这些细胞的保护作用丧失而导致男性乳腺癌的发生。然而，不能排除突变的雄激素受体的DNA结合特性改变对雌激素调节基因的激活作用。
