Maggiolini Marcello, Vivacqua Adele, Fasanella Giovanna, Recchia Anna Grazia, Sisci Diego, Pezzi Vincenzo, Montanaro Daniela, Musti Anna Maria, Picard Didier, Andò Sebastiano
Department of Pharmaco-Biology, University of Calabria, 87030 Rende (CS), Italy.
J Biol Chem. 2004 Jun 25;279(26):27008-16. doi: 10.1074/jbc.M403588200. Epub 2004 Apr 16.
A growing body of evidence concerning estrogen effects cannot be explained by the classic model of hormone action, which involves the binding to estrogen receptors (ERs) alpha and ERbeta and the interaction of the steroid-receptor complex with specific DNA sequences associated with target genes. Using c-fos proto-oncogene expression as an early molecular sensor of estrogen action in ERalpha-positive MCF7 and ER-negative SKBR3 breast cancer cells, we have discovered that 17beta-estradiol (E2), and the two major phytoestrogens, genistein and quercetin, stimulate c-fos expression through ERalpha as well as through an ER-independent manner via the G protein-coupled receptor homologue GPR30. The c-fos response is repressed in GPR30-expressing SKBR3 cells transfected with an antisense oligonucleotide against GPR30 and reconstituted in GPR30-deficient MDA-MB 231 and BT-20 breast cancer cells transfected with a GPR30 expression vector. GPR30-dependent activation of ERK1/2 by E2 and phytoestrogens occurs via a Gbetagamma-associated pertussis toxin-sensitive pathway that requires both Src-related and EGF receptor tyrosine kinase activities. The ability of E2 and phytoestrogens to regulate the expression of growth-related genes such as c-fos even in the absence of ER has interesting implications for understanding breast cancer progression.
越来越多有关雌激素作用的证据无法用经典的激素作用模型来解释，该经典模型涉及雌激素与α和β雌激素受体（ERs）的结合以及类固醇 - 受体复合物与靶基因相关的特定DNA序列的相互作用。利用原癌基因c - fos的表达作为ERα阳性的MCF7和ER阴性的SKBR3乳腺癌细胞中雌激素作用的早期分子传感器，我们发现17β - 雌二醇（E2）以及两种主要的植物雌激素染料木黄酮和槲皮素，通过ERα以及经由G蛋白偶联受体同系物GPR30以不依赖ER的方式刺激c - fos表达。在用针对GPR30的反义寡核苷酸转染的表达GPR30的SKBR3细胞中，c - fos反应受到抑制，而在用GPR30表达载体转染的缺乏GPR30的MDA - MB 231和BT - 20乳腺癌细胞中，c - fos反应得以重建。E2和植物雌激素通过E2和植物雌激素通过与Gβγ相关的百日咳毒素敏感途径对ERK1/2进行GPR30依赖性激活，该途径需要Src相关和表皮生长因子受体酪氨酸激酶活性。即使在没有ER的情况下，E2和植物雌激素调节生长相关基因如c - fos表达的能力对于理解乳腺癌进展具有有趣的意义。
