Hayashi Takanori, Hikichi Masahiro, Yukitake Jun, Harada Nobuhiro, Utsumi Toshiaki
Department of Biochemistry, School of Medicine, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Department of Breast Surgery, School of Medicine, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Oncol Lett. 2017 Dec;14(6):8060-8065. doi: 10.3892/ol.2017.7216. Epub 2017 Oct 18.
Aromatase inhibitors (AIs) are effective endocrine therapeutics for postmenopausal women with estrogen receptor (ER)α-positive breast cancer. However, the efficacy of the treatment is often limited by the onset of AI resistance, owing to the phosphorylation of ERα 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 ERα 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 ERα Ser167 phosphorylation and estradiol (E)-independent cell growth. The present study investigated the potential relevance of PP2A in E deprivation-resistant MCF-7 cells. E depletion reduced the susceptibility of MCF-7 cells to inhibitors of mechanistic target of rapamycin (mTOR) and significantly increased ERα Ser167 phosphorylation and decreased expression of PP2A. Conversely, long-term E-deprived (LTED) MCF-7 cells, a model of AI-resistant breast cancer, exhibited decreased ERα Ser167 phosphorylation and further upregulation of PP2A in E-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.
芳香化酶抑制剂（AIs）是治疗雌激素受体（ER）α阳性绝经后乳腺癌女性的有效内分泌疗法。然而，由于ERα丝氨酸167（Ser167）磷酸化，治疗效果常常受到AI耐药性出现的限制。先前的研究表明，在AI耐药乳腺癌模型中发生了磷酸肌醇-3激酶/RAC丝氨酸/苏氨酸蛋白激酶信号通路的过度激活，这与Ser167处ERα磷酸化水平升高一致。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。先前的一项研究表明，PP2A抑制可降低ERα Ser167磷酸化和雌二醇（E）非依赖性细胞生长。本研究调查了PP2A在抗E剥夺的MCF-7细胞中的潜在相关性。E剥夺降低了MCF-7细胞对雷帕霉素作用靶点（mTOR）抑制剂的敏感性，并显著增加了ERα Ser167磷酸化，降低了PP2A的表达。相反，长期E剥夺（LTED）的MCF-7细胞是AI耐药乳腺癌的模型，在含E培养基中表现出ERα Ser167磷酸化降低和PP2A进一步上调。PP2A激活剂福司可林（FSK）通过增强mTOR抑制剂依维莫司（Eve）的作用，显著抑制LTED细胞增殖。总之，本研究提供了进一步的证据，表明PP2A是AI耐药乳腺癌的治疗靶点。
