Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells
Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells
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DOI：
10.3892/ol.2017.7216
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发表时间：
2017-12-01
期刊：
影响因子：
2.9
通讯作者：
Utsumi, Toshiaki
中科院分区：
文献类型：
--
作者：
Hayashi, Takanori;Hikichi, Masahiro;Utsumi, Toshiaki
芳香酶抑制剂 (AI) 是治疗患有雌激素受体 (ER)α 阳性乳腺癌的绝经后女性的有效内分泌疗法。然而，由于 ER α 丝氨酸 167 (Ser167) 磷酸化，治疗效果常常受到 AI 耐药性的发生的限制。先前的研究表明，在 AI 耐药乳腺癌模型中，磷酸肌醇 3 激酶/RAC 丝氨酸/苏氨酸蛋白激酶信号通路过度激活，这与 ER α Ser167 磷酸化水平升高相一致。肿瘤抑制因子丝氨酸/苏氨酸蛋白磷酸酶 2A (PP2A) 调节磷脂酰肌醇 3-激酶/RAC 丝氨酸/苏氨酸蛋白激酶信号通路。先前的研究表明，PP2A 抑制会降低 ER α Ser167 磷酸化和雌二醇 (E-2) 独立的细胞生长。本研究调查了 PP2A 在 E-2 剥夺抗性 MCF-7 细胞中的潜在相关性。 E-2 耗竭降低了 MCF-7 细胞对雷帕霉素机械靶标 (mTOR) 抑制剂的敏感性，并显着增加 ER α Ser167 磷酸化并降低 PP2A 表达。相反，长期 E2 剥夺 (LTED) MCF-7 细胞（一种 AI 抗性乳腺癌模型）在含有 E-2 的培养基中表现出 ERa Ser167 磷酸化降低和 PP2A 进一步上调。 PP2A 激活剂毛喉素 (FSK) 通过增强 mTOR 抑制剂依维莫司 (Eve) 的作用，显着抑制 LTED 细胞增殖。总之，本研究进一步证明 PP2A 是 AI 耐药乳腺癌的治疗靶点。
Aromatase inhibitors (AIs) are effective endocrine therapeutics for postmenopausal women with estrogen receptor (ER)alpha-positive breast cancer. However, the efficacy of the treatment is often limited by the onset of AI resistance, owing to the phosphorylation of ER alpha serine 167 (Ser167). Previous studies have indicated that hyperactivation of the phosphoinositide-3 kinase/RAC serine/threonine-protein kinase signaling pathway occurs in AI-resistant breast cancer models, which coincides with elevated levels of ER alpha phosphorylation at Ser167. The tumor suppressor serine/threonine-protein phosphatase 2A (PP2A) regulates the phosphatidylinositol 3-kinase/RAC serine/threonine-protein kinase signaling pathway. A previous study indicated that PP2A inhibition decreased ER alpha Ser167 phosphorylation and estradiol (E-2)-independent cell growth. The present study investigated the potential relevance of PP2A in E-2 deprivation-resistant MCF-7 cells. E-2 depletion reduced the susceptibility of MCF-7 cells to inhibitors of mechanistic target of rapamycin (mTOR) and significantly increased ER alpha Ser167 phosphorylation and decreased expression of PP2A. Conversely, long-term E2-deprived (LTED) MCF-7 cells, a model of AI-resistant breast cancer, exhibited decreased ERa Ser167 phosphorylation and further upregulation of PP2A in E-2-containing medium. The PP2A activator forskolin (FSK) significantly inhibited LTED cell proliferation by increasing the effect of everolimus (Eve), an mTOR inhibitor. In summary, the present study provides further evidence that PP2A represents a therapeutic target for AI-resistant breast cancer.