Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

Hayashi,Takanori; Hikichi,Masahiro; Yukitake,Jun; Harada,Nobuhiro; Utsumi,Toshiaki

doi:10.3892/ol.2017.7216

Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

Authors:
- Takanori Hayashi
- Masahiro Hikichi
- Jun Yukitake
- Nobuhiro Harada
- Toshiaki Utsumi
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Affiliations: 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, Department of Clinical Immunology, School of Health Sciences, Fujita Health University, Toyoake, Aichi 470‑1192, Japan
Published online on: October 18, 2017 https://doi.org/10.3892/ol.2017.7216
Pages: 8060-8065

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Abstract

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 (E2)‑independent cell growth. The present study investigated the potential relevance of PP2A in E2 deprivation‑resistant MCF‑7 cells. E2 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 E2‑deprived (LTED) MCF‑7 cells, a model of AI‑resistant breast cancer, exhibited decreased ERα Ser167 phosphorylation and further upregulation of PP2A in E2‑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.

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