Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Br J Pharmacol. 2013 May;169(1):167-78. doi: 10.1111/bph.12122.
Oestrogen receptor alpha (ERα) binds to different ligand which can function as complete/partial oestrogen-agonist or antagonist. This depends on the chemical structure of the ligands which modulates the transcriptional activity of the oestrogen-responsive genes by altering the conformation of the liganded-ERα complex. This study determined the molecular mechanism of oestrogen-agonistic/antagonistic action of structurally similar ligands, bisphenol (BP) and bisphenol A (BPA) on cell proliferation and apoptosis of ERα + ve breast cancer cells.
DNA was measured to assess the proliferation and apoptosis of breast cancer cells. RT-PCR and ChIP assays were performed to quantify the transcripts of TFF1 gene and recruitment of ERα and SRC3 at the promoter of TFF1 gene respectively. Molecular docking was used to delineate the binding modes of BP and BPA with the ERα. PCR-based arrays were used to study the regulation of the apoptotic genes.
BP and BPA induced the proliferation of breast cancer cells; however, unlike BPA, BP failed to induce apoptosis. BPA consistently acted as an agonist in our studies but BP exhibited mixed agonistic/antagonistic properties. Molecular docking revealed agonistic and antagonistic mode of binding for BPA and BP respectively. BPA treatment resembled E2 treatment in terms of PCR-based regulation of apoptotic genes whereas BP was similar to 4OHT treatment.
The chemical structure of ERα ligand determines the agonistic or antagonistic biological responses by the virtue of their binding mode, conformation of the liganded-ERα complex and the context of the cellular function.
雌激素受体 alpha（ERα）与不同的配体结合，这些配体可以作为完全/部分雌激素激动剂或拮抗剂发挥作用。这取决于配体的化学结构，通过改变配体结合的 ERα 复合物的构象来调节雌激素反应基因的转录活性。本研究旨在确定结构相似的配体双酚（BP）和双酚 A（BPA）对 ERα+ve 乳腺癌细胞增殖和凋亡的雌激素激动/拮抗作用的分子机制。
通过测量 DNA 来评估乳腺癌细胞的增殖和凋亡。通过 RT-PCR 和 ChIP 测定分别定量 TFF1 基因的转录物和 ERα 和 SRC3 在 TFF1 基因启动子处的募集。分子对接用于描绘 BP 和 BPA 与 ERα 的结合模式。基于 PCR 的阵列用于研究凋亡基因的调节。
BP 和 BPA 诱导乳腺癌细胞增殖；然而，与 BPA 不同，BP 未能诱导凋亡。在我们的研究中，BPA 一直作为激动剂起作用，但 BP 表现出混合激动/拮抗特性。分子对接显示 BPA 和 BP 分别具有激动剂和拮抗剂结合模式。BPA 处理在基于 PCR 的凋亡基因调节方面类似于 E2 处理，而 BP 类似于 4OHT 处理。
ERα 配体的化学结构通过其结合模式、配体结合的 ERα 复合物的构象以及细胞功能的背景决定了激动剂或拮抗剂的生物学反应。
