Pfeffer U, Fecarotta E, Vidali G
Laboratory of Molecular Biology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Cancer Res. 1995 May 15;55(10):2158-65.
Mammary cancers often develop into a hormone-independent and antagonist-resistant growth phase. The molecular mechanisms of this transition are not clear. Recently, it has been proposed that estrogen receptor variants derived from alternative splicing might lead to dominant positive transcription factors acting on estrogen response elements, even in the absence of the hormone. We show here the comprehensive analysis of expression of estrogen receptor variants lacking internal exons in the estrogen receptor-positive mammary carcinoma cell line MCF-7, in a tumor sample, and in healthy breast tissue taken from reduction surgery. Variants are identified by reverse transcription PCR and hybridization to exon-specific oligonucleotide probes. In MCF-7 cells we detected 10 variants including 5 that have not been described before. Skipping one, two, or three exons occurs. The major variants detected in the cell line are also present in normal and neoplastic tissues. Quantitative variations allow no conclusions of a potential involvement of the variants in neoplastic processes. Rather, the variants appear to be present normally and thus might have a physiological role. Given the expression of the variants in normal tissue, and given the expression of potentially dominant positive variants in conjunction with potentially dominant negative ones, we suggest that these variants do not account for hormone antagonist resistance.
乳腺癌常常发展为激素非依赖性和拮抗剂抗性生长阶段。这种转变的分子机制尚不清楚。最近，有人提出，源自可变剪接的雌激素受体变体可能导致即使在没有激素的情况下也能作用于雌激素反应元件的显性正转录因子。我们在此展示了对雌激素受体阳性乳腺癌细胞系MCF-7、肿瘤样本以及取自缩乳手术的健康乳腺组织中缺乏内部外显子的雌激素受体变体表达的全面分析。通过逆转录PCR和与外显子特异性寡核苷酸探针杂交来鉴定变体。在MCF-7细胞中，我们检测到10种变体，其中5种此前未曾描述过。存在跳过一个、两个或三个外显子的情况。在细胞系中检测到的主要变体也存在于正常组织和肿瘤组织中。定量变化无法得出这些变体可能参与肿瘤形成过程的结论。相反，这些变体似乎正常存在，因此可能具有生理作用。鉴于这些变体在正常组织中的表达，以及潜在的显性正变体与潜在的显性负变体的共同表达，我们认为这些变体并不能解释激素拮抗剂抗性。
