School of Basic Medical Sciences, Guilin Medical University, Guilin, China.
Department of Emergency, First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Mol Carcinog. 2018 Jul;57(7):817-830. doi: 10.1002/mc.22531. Epub 2018 May 2.
For postmenopausal cardiovascular disease, long-term estrogen therapy may increase the risk of breast cancer. To reduce this risk, estrogen may be replaced with the phytoestrogen formononetin, but how formononetin acts on vascular endothelial cells (ECs) and breast cancer cells is unclear. Here, we show that low concentrations of formononetin induced proliferation and inhibited apoptosis more strongly in cultured human umbilical vein endothelial cells (HUVECs) than in breast cancer cells expressing estrogen receptor α (ERα) (MCF-7, BT474) or not (MDA-MB-231), and that this differential stimulation was associated with miR-375 up-regulation in HUVECs. For the first time, we demonstrate the presence of a feedback loop involving miR-375, ras dexamethasone-induced 1 (RASD1), and ERα in normal HUVECs, and we show that formononetin stimulated this feedback loop in HUVECs but not in MCF-7 or BT474 cells. In all three cell lines, formononetin increased Akt phosphorylation and Bcl-2 expression. Inhibiting miR-375 blocked these changes and increased proliferation in HUVECs, but not in MCF-7 or BT474 cells. In ovariectomized rats, formononetin increased uterine weight and caused similar changes in levels of miR-375, RASD1, ERα, and Bcl-2 in aortic ECs as in cultured HUVECs. In mice bearing MCF-7 xenografts, tumor growth was stimulated by 17β-estradiol but not by formononetin. These results suggest selective action of formononetin in ECs (proliferation stimulation and apoptosis inhibition) relative to breast cancer cells, possibly via a feedback loop involving miR-375, RASD1, and ERα. This differential effect may explain why formononetin may not increase the risk of postmenopausal breast cancer.
对于绝经后心血管疾病，长期雌激素治疗可能会增加乳腺癌的风险。为了降低这种风险，雌激素可能会被植物雌激素芒柄花素所取代，但芒柄花素如何作用于血管内皮细胞（ECs）和乳腺癌细胞尚不清楚。在这里，我们表明，低浓度的芒柄花素在培养的人脐静脉内皮细胞（HUVECs）中比在表达雌激素受体α（ERα）（MCF-7、BT474）或不表达（MDA-MB-231）的乳腺癌细胞中更强烈地诱导增殖并抑制凋亡，并且这种差异刺激与 HUVECs 中 miR-375 的上调有关。我们首次证明了在正常 HUVECs 中存在涉及 miR-375、ras 地塞米松诱导 1（RASD1）和 ERα 的反馈回路，并且我们表明芒柄花素刺激了该反馈回路在 HUVECs 中，但不在 MCF-7 或 BT474 细胞中。在所有三种细胞系中，芒柄花素均增加了 Akt 磷酸化和 Bcl-2 的表达。抑制 miR-375 阻断了这些变化并增加了 HUVECs 的增殖，但在 MCF-7 或 BT474 细胞中没有。在去卵巢大鼠中，芒柄花素增加了子宫重量，并导致培养的 HUVECs 和主动脉 ECs 中 miR-375、RASD1、ERα 和 Bcl-2 的水平发生类似变化。在携带 MCF-7 异种移植物的小鼠中，17β-雌二醇刺激肿瘤生长，但芒柄花素没有。这些结果表明，芒柄花素在 ECs 中的选择性作用（增殖刺激和凋亡抑制）相对于乳腺癌细胞，可能通过涉及 miR-375、RASD1 和 ERα 的反馈回路。这种差异作用可能解释了为什么芒柄花素不会增加绝经后乳腺癌的风险。
