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Upregulation of CIP2A in estrogen depletion-resistant breast cancer cells treated with low-dose everolimus.

Authors
  • Nishio, Eiji1
  • Hayashi, Takanori2
  • Akaza, Mao2
  • Hisatomi, Yukiko2
  • Hikichi, Masahiro3
  • Fujii, Takuma1
  • Utsumi, Toshiaki3
  • Harada, Nobuhiro2
  • Shimono, Yohei2
  • 1 Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, Toyoake, Japan. , (Japan)
  • 2 Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan. , (Japan)
  • 3 Department of Breast Surgery, Fujita Health University School of Medicine, Toyoake, Japan. , (Japan)
Type
Published Article
Journal
FEBS Open Bio
Publisher
Wiley (John Wiley & Sons)
Publication Date
Oct 01, 2020
Volume
10
Issue
10
Pages
2072–2080
Identifiers
DOI: 10.1002/2211-5463.12956
PMID: 32810922
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Everolimus (EVE), an inhibitor of mammalian target of rapamycin, is an emerging second-line therapeutic option for hormone therapy-resistant breast cancers. However, some patients do not respond to EVE, whereas in others it exacerbates the disease. Cellular inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that can promote cancer cell growth and apoptosis resistance. Although CIP2A is upregulated in hormone-related cancers, such as breast cancer, little is known about potential anti-tumor effects of downregulating CIP2A. As a model to study the resistance of breast cancer cells to hormone treatment, we previously established clones of long-term estrogen depletion-resistant MCF-7 (LTED) cells. Here, we selected three clones highly responsive to EVE and three clones poorly responsive to EVE. When cells were treated with EVE, CIP2A mRNA expression was decreased in highly responsive EVE clones (DC-cells) whereas it was increased in poorly responsive EVE clones (IC-cells). Using Kaplan-Meier survival plots, we report that high expression of CIP2A was associated with significantly reduced overall survival in patients with luminal A breast cancer. In IC-cells, cell growth was enhanced upon EVE treatment whereas an EVE range of 0.1-100 nm decreased growth in DC-cells. The mRNA expression of genes involved in epithelial-mesenchymal transition (EMT) such as CDH1, CLDN3, and CK19 was significantly decreased in IC-cells, but remained unchanged in DC-cells. These findings highlight a relationship between CIP2A and EMT in the intrinsic resistance of hormone therapy-resistant breast cancers to EVE. © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

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