ESTROGEN-RECEPTOR GENE ANALYSIS IN ESTROGEN RECEPTOR-POSITIVE AND RECEPTOR-NEGATIVE PRIMARY BREAST-CANCER
ESTROGEN-RECEPTOR GENE ANALYSIS IN ESTROGEN RECEPTOR-POSITIVE AND RECEPTOR-NEGATIVE PRIMARY BREAST-CANCER
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DOI：
10.1093/jnci/87.6.446
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发表时间：
1995-03-15
影响因子：
10.3
通讯作者：
PARL, FF
中科院分区：
文献类型：
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作者：
ROODI, N;BAILEY, LR;PARL, FF
背景：在乳腺癌患者中，约三分之二的肿瘤为雌激素受体（ER）阳性，三分之一为 ER 阴性，导致 ER 阴性表型的分子机制知之甚少，几乎所有 ER 阴性和约 40% ER 阳性癌症对内分泌治疗有耐药性，目的：在本研究中，我们检查了 ER 阳性和 ER 阴性原发性乳腺肿瘤中 ER 基因的整个编码区，以确定是否缺失/插入或点突变可能是 ER 阴性表型的原因，方法：我们在 118 个 ER 阳性和 70 个 ER 阴性原发性乳腺肿瘤中扩增了 ER 基因的外显子 1 至 8，并通过单链构象多态性分析、变性梯度凝胶电泳和 DNA 测序寻找突变，结果：10 个 ER 阴性和 ER 阳性肿瘤均存在中性多态性。 [TCT-->TCC(Ser)]、87[GCG-->GCC(Ala)]、243[CGC-->CGT(Arg)]、325[CCC-->CCG(Pro)]和594[ACA-->ACG(Thr)]。任何多态性等位基因与 ER 表型或其他临床病理参数（包括肿瘤类型、大小、分级或分期）均不相关。然而，密码子 325 的多态性显示与乳腺癌家族史有很强的相关性 (P = .0005)，这种关联在绝经前和绝经后患者中均观察到，尽管对外显子 1 至 8 进行了广泛搜索，但我们发现密码子 69 [AAC (Asn)-->AAG (Lys)] 和 396 [ATG] 中没有删除/插入，只有两个错义突变(Met)-->GTG(Val)]相同ER阴性肿瘤，因此，只有1%的原发性乳腺癌存在ER基因点突变，结论：在大多数原发性乳腺癌中，ER阴性表型并不是ER基因编码区突变的结果，而是由于转录或转录后水平的ER表达缺陷所致。意义：之前报道的相关性以及我们目前的发现表明，有必要进行进一步的研究，以了解 ER 基因位点与遗传性乳腺癌之间可能的联系。
Background: In breast cancer patients, about two thirds of the tumors are estrogen receptor (ER)-positive and one third are ER-negative, The molecular mechanisms leading to the ER-negative phenotype are poorly understood, Nearly all ER-negative and about 40% of ER-positive cancers are resistant to endocrine therapy, Purpose: In this study, we examined the entire coding region of the ER gene in ER-positive and ER-negative primary breast tumors to determine whether deletions/insertions or point mutations might account for the ER-negative phenotype, Methods: We amplified exons 1 through 8 of the ER gene in 118 ER-positive and 70 ER-negative primary breast tumors and searched for mutations by single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, and DNA sequencing, Results: Both ER-negative and ER-positive tumors con-neutral polymorphisms in 10 [TCT-->TCC (Ser)], 87 [GCG-->GCC (Ala)], 243 [CGC-->CGT (Arg)], 325 [CCC-->CCG (Pro)], and 594 [ACA-->ACG (Thr)]. There was no correlation of any of the polymorphic alleles with the ER phenotype or other clinicopathologic parameters including tumor type, size, grade, or stage. However, the polymorphism in codon 325 showed a strong association with a family history of breast cancer (P = .0005), This association was observed both in premenopausal and postmenopausal patients, Despite extensive searching in exons 1 through 8, we found no deletions/insertions and only two missense mutations in codons 69 [AAC (Asn)-->AAG (Lys)] and 396 [ATG (Met)-->GTG (Val)] of the same ER-negative tumor, Thus, only 1% of the primary breast cancers had point mutations in the ER gene, Conclusions: In the majority of primary breast cancers, the ER-negative phenotype is not the result of mutations in the coding region of the ER gene, but is due to deficient ER expression at the transcriptional or post-transcriptional level. Implications: The correlation reported previously, as well as our current findings, suggest that further investigations are warranted to understand the possible linkage of the ER gene locus to hereditary breast cancer.