Polymorphisms of the estrogen receptor gene in familial breast cancer

1)与雌激素受体基因的可能连锁我们利用雌激素受体基因的3个遗传标记（ESR，密码子10,325点变异）和BRCA1区域的4个标记（D17S250, D17S846, D17S855, D17S579），证实了4个日本乳腺癌家族可能与雌激素受体（ER）基因存在连锁。在四个家庭中的两个中，受影响的女性共享ER基因的等位基因类型，但没有共享BRCA1等位基因类型。不幸的是，我们在这些家庭中没有发现任何ER基因的突变。2)雌激素受体基因与乳腺癌易感性我们之前在1号外显子和4号外显子中发现了2种序列变异，分别在密码子10 （TCT到TCC）和密码子325 （CCC到CCG）上发现了2种沉默突变。虽然这些多态性位点的频率与激素受体状态和其他临床病理因素无关，但密码子325的变异在乳腺癌患者中比在非癌症对照病例中更常见（P=0.057）。由于密码子325位于激素结合结构域，这个多态性位点似乎与乳腺癌易感性相关，可能影响内质网功能。或者，这种多态性可能与编码或不可检测的调节突变的连锁不平衡。3)激素依赖性的丧失和ER基因的改变在乳腺癌治疗过程中可能出现激素依赖性是一个实质性的问题。然而，内质网基因的遗传改变，如错义、无义突变，不会影响内质网功能的丧失。DNA甲基化常见于ER阴性肿瘤患者。有研究认为，内质网基因的表观遗传改变、选择性剪接变异和DNA甲基化可能影响内质网功能。此外，最近克隆了一种新的雌激素受体ERbeta，因此ERbeta可能影响经典ER （ER*）功能。我们将在未来关注这些领域。

1)Possible linkage to the estrogen receptor geneWe demonstrated a possible linkage to the estrogen receptor (ER) gene in four Japanese breast cancer families, using three genetic markers (ESR,point variations of codon 10,325) in the ER gene and four markers (D17S250, D17S846, D17S855, D17S579) in the BRCA1 region. In two of the four families, the affected women shared allele type of the ER gene, but did not share BRCA1 allele types. Unfortunately, we could not find out any mutation of the ER gene in the families.2)Estrogen receptor gene and breast cancer susceptibilityWe previously found 2 types of sequence variants in exon 1 and exon 4, indicated two silent mutations in codon 10 (TCT to TCC) and codon 325 (CCC to CCG), respectively. Although the frequency of these polymorphic sites were not correlated with hormone receptor status and other clinico-pathologic factors, the variant in codon 325 tended to be seen more frequently in breast cancer patients than in non-cancer control cases (P=0.057). Since codon 325 is located in the hormone binding domain, this polymorphic site which appears to correlate with breast cancer susceptibility may affect ER function. Alternatively, this polymorphism may be in linkage disequilibrium with a coding or undetectable regulatory mutation.3)Loss of hormone dependency and alterations of the ER geneIt is a substantial problem that hormone independence may occur during breast cancer treatment. However, genetic alterations of the ER gene, such as missense, nonsense mutations, could not affect the loss of ER function. DNA methylation frequently occurred in the patients with ER negative tumor. It has been suggested that the epigenetic changes, alternative splice variants and DNA methylation of the ER gene, may affect ER function. Additionally, a novel estrogen receptor, ERbeta, was recently cloned, so ERbeta may affect the classical ER (ER*) function. We will focus these area in the future.