CNR, National Research Council of Italy, Institute of Molecular Biology and Pathology, Rome, Italy.
Biomed Pharmacother. 2011 Jul;65(4):307-12. doi: 10.1016/j.biopha.2011.03.007. Epub 2011 May 30.
In the present report, we investigated the action of retinoic acid (RA) on the transactivation of the epidermal growth factor receptor (EGFR) gene promoter. In a previous study, we showed that the estrogen receptor (ER) α activated by 17β-estradiol (E₂) increased EGFR expression by enhancing the binding of the transcription factor Sp1 to the EGFR minimal promoter in HeLa cells. Here, we demonstrate that ligand-activated RA receptor (RAR) α inhibited EGFR transactivation by competing with Sp1 for binding to the same promoter fragment in the same cell model. When RARα and ERα were coexpressed, the inhibitory effect of RA on transactivation of the EGFR promoter counteracted the enhancement induced by E₂-activated ERα and became more pronounced in the presence of ligand-free ERα. In the MCF7 breast cancer cell line, which endogenously expresses RARα and ERα, RA exerted anti-proliferative effects in the presence of ligand-free ERα. Moreover, interplay between the pathways mediated by the two receptors was observed, as RA counteracted E₂-induced cell proliferation. Our results suggest that the interference with the activity of Sp1 on the EGFR promoter could be related to the observed RA-mediated growth suppression of breast cancer cells.
在本报告中，我们研究了视黄酸 (RA) 对表皮生长因子受体 (EGFR) 基因启动子转录激活的作用。在之前的研究中，我们表明，17β-雌二醇 (E₂) 激活的雌激素受体 (ER)α 通过增强转录因子 Sp1 与 HeLa 细胞中 EGFR 最小启动子的结合，增加了 EGFR 的表达。在这里，我们证明，配体激活的视黄酸受体 (RAR)α 通过与 Sp1 竞争结合相同的启动子片段，抑制了 EGFR 的转录激活。当 RARα 和 ERα 共表达时，RA 对 EGFR 启动子转录激活的抑制作用抵消了由 E₂ 激活的 ERα 诱导的增强作用，并且在没有配体的 ERα 存在下更为明显。在 MCF7 乳腺癌细胞系中，内源性表达 RARα 和 ERα，RA 在没有配体的 ERα 存在下发挥抗增殖作用。此外，还观察到两条途径之间的相互作用，因为 RA 抵消了 E₂ 诱导的细胞增殖。我们的结果表明，对 EGFR 启动子上 Sp1 活性的干扰可能与观察到的 RA 介导的乳腺癌细胞生长抑制有关。
