Treeck Oliver, Juhasz-Boess Ingolf, Lattrich Claus, Horn Felicitas, Goerse Regina, Ortmann Olaf
Department of Obstetrics and Gynecology, University of Regensburg, Landshuter Str. 65, 93053 Regensburg, Germany.
Breast Cancer Res Treat. 2008 Aug;110(3):507-20. doi: 10.1007/s10549-007-9749-7. Epub 2007 Sep 18.
Estrogen receptor beta gene codes for a variety of transcript isoforms resulting from alternative splicing, which are expressed both in mammary gland and in breast cancer cells. We studied the function of two exon-deleted ERbeta isoforms recently identified by our group in comparison to ERbeta1 in regulation of growth, apoptosis and gene expression of two breast cancer cell lines with different ERalpha status. Overexpression of ERbeta1, but not of the exon-deleted variants exerted strong antitumoral effects both on ERalpha-positive MCF-7 and ERalpha-negative SK-BR-3 cells. ERbeta1 overexpression slowed growth of MCF-7 and SK-BR-3 cells in the absence of E2 and also inhibited E2-triggered growth stimulation of MCF-7 cells, but overexpression of the exon-skipped variants did not affect cell growth. Whereas overexpression of ERbeta1 triggered an increased basal and tamoxifen-induced apoptosis of MCF-7 and SK-BR-3 cells, the isoforms ERbetadelta125 or ERbetadelta1256 did not affect cellular tamoxifen response. The observed lack of function of the exon-deleted variants in terms of regulation of proliferation was accompanied both by their inability to affect expression of cyclins D1 and A2, p21 (WAF1) and PR and their disability to modulate estrogen response element (ERE) activation. In contrast, our results demonstrating antitumoral effects of ERbeta1 on breast cancer cells with different ERalpha-status support the hypothesis that ERbeta is able to exert antitumoral actions both on ERalpha-positive and -negative breast cancer cells.
雌激素受体β基因编码多种由可变剪接产生的转录异构体，这些异构体在乳腺和乳腺癌细胞中均有表达。我们研究了我们小组最近鉴定的两种外显子缺失的ERβ异构体与ERβ1相比，在调节两种具有不同ERα状态的乳腺癌细胞系的生长、凋亡和基因表达方面的功能。ERβ1的过表达，而非外显子缺失变体的过表达，对ERα阳性的MCF-7细胞和ERα阴性的SK-BR-3细胞均具有强大的抗肿瘤作用。在没有E2的情况下，ERβ1过表达减缓了MCF-7和SK-BR-3细胞的生长，并且也抑制了E2触发的MCF-7细胞的生长刺激，但外显子跳跃变体的过表达不影响细胞生长。虽然ERβ1的过表达引发了MCF-7和SK-BR-3细胞基础及他莫昔芬诱导的凋亡增加，但异构体ERβδ125或ERβδ1256不影响细胞对他莫昔芬的反应。在外显子缺失变体调节增殖方面观察到的功能缺失，同时伴随着它们无法影响细胞周期蛋白D1和A2、p21（WAF1）和PR的表达以及它们调节雌激素反应元件（ERE）激活的能力丧失。相比之下，我们的结果表明ERβ1对具有不同ERα状态的乳腺癌细胞具有抗肿瘤作用，支持了ERβ能够对ERα阳性和阴性乳腺癌细胞都发挥抗肿瘤作用的假说。
