Research Papers:

Forskolin increases the effect of everolimus on aromatase inhibitor-resistant breast cancer cells

Takanori Hayashi _, Masahiro Hikichi, Jun Yukitake, Toru Wakatsuki, Eiji Nishio, Toshiaki Utsumi and Nobuhiro Harada

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Oncotarget. 2018; 9:23451-23461. https://doi.org/10.18632/oncotarget.25217

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Takanori Hayashi1, Masahiro Hikichi2,*, Jun Yukitake3, Toru Wakatsuki4, Eiji Nishio5, Toshiaki Utsumi2,* and Nobuhiro Harada1

1Department of Biochemistry, School of Medicine, Fujita Health University, Aichi, Japan

2Department of Breast Surgery, School of Medicine, Fujita Health University, Aichi, Japan

3Department of Clinical Immunology, School of Health Sciences, Fujita Health University, Aichi, Japan

4Department of Health Science, School of Medicine, Fujita Health University, Aichi, Japan

5Department of Obstetrics and Gynecology, School of Medicine, Fujita Health University, Aichi, Japan

*These authors contributed equally to this work

Correspondence to:

Takanori Hayashi, email: [email protected]

Keywords: everolimus; aromatase inhibitors resistance; long-term estrogen-deprived cells; PP2A; breast cancer

Received: October 17, 2017     Accepted: April 06, 2018     Published: May 04, 2018


Aromatase inhibitor (AI) resistance is a major obstacle in the treatment of estrogen receptor-positive breast cancer. Everolimus (EVE) ameliorates AI-resistant breast cancer and is therefore used in cancer treatment. However, some patients show resistance to EVE. Here, we used 30 clones of long-term estrogen-deprived (LTED) MCF-7 cells as a model of AI-resistant breast cancer. We examined changes in protein phosphatase type 2A (PP2A) and cancerous inhibitor of PP2A (CIP2A), a negative regulator of PP2A, in LTED cells treated with EVE. In LTED cells with high sensitivity to EVE, CIP2A expression decreased at low EVE concentrations; however, in LTED cells poorly sensitive to EVE, CIP2A and PP2A did not change upon exposure to EVE. Therefore, we hypothesized that there is a relation between expression of CIP2A and sensitivity to EVE. Knockdown of CIP2A increased the sensitivity to EVE in three clones poorly sensitive to EVE. Additionally, we found that treatment with FSK, which activates PP2A, increased the sensitivity of the cells to EVE. Our data point to CIP2A and PP2A as novel therapeutic targets for AI-resistant breast cancer.

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