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

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 ER α 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 repre- sents a therapeutic target for AI-resistant breast cancer.

Original languageEnglish
Pages (from-to)8060-8065
Number of pages6
JournalOncology Letters
Volume14
Issue number6
DOIs
Publication statusPublished - 01-12-2017

Fingerprint

Protein Phosphatase 2
Estrogen Receptors
Serine
Aromatase Inhibitors
Estradiol
Up-Regulation
Phosphorylation
Breast Neoplasms
MCF-7 Cells
Protein-Serine-Threonine Kinases
Sirolimus
Phosphatidylinositol 3-Kinase
1-Phosphatidylinositol 4-Kinase
Colforsin
Threonine
Cell Proliferation
Therapeutics
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Hayashi, Takanori ; Hikichi, Masahiro ; Yukitake, Jun ; Harada, Nobuhiro ; Utsumi, Toshiaki. / Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells. In: Oncology Letters. 2017 ; Vol. 14, No. 6. pp. 8060-8065.
@article{c170db62c6bd4df68dffda8933b2e983,
title = "Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells",
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 ER α 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 repre- sents a therapeutic target for AI-resistant breast cancer.",
author = "Takanori Hayashi and Masahiro Hikichi and Jun Yukitake and Nobuhiro Harada and Toshiaki Utsumi",
year = "2017",
month = "12",
day = "1",
doi = "10.3892/ol.2017.7216",
language = "English",
volume = "14",
pages = "8060--8065",
journal = "Oncology Letters",
issn = "1792-1074",
publisher = "Spandidos Publications",
number = "6",

}

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.

In: Oncology Letters, Vol. 14, No. 6, 01.12.2017, p. 8060-8065.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

AU - Hayashi, Takanori

AU - Hikichi, Masahiro

AU - Yukitake, Jun

AU - Harada, Nobuhiro

AU - Utsumi, Toshiaki

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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 ER α 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 repre- sents a therapeutic target for AI-resistant breast cancer.

AB - 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 ER α 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 repre- sents a therapeutic target for AI-resistant breast cancer.

UR - http://www.scopus.com/inward/record.url?scp=85032710093&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032710093&partnerID=8YFLogxK

U2 - 10.3892/ol.2017.7216

DO - 10.3892/ol.2017.7216

M3 - Article

AN - SCOPUS:85032710093

VL - 14

SP - 8060

EP - 8065

JO - Oncology Letters

JF - Oncology Letters

SN - 1792-1074

IS - 6

ER -