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Clinical and Translational Oncology
Published in: Clinical and Translational Oncology 8/2019

Open Access 01-08-2019 | Breast Cancer | Research Article

Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1

Authors: Y. Wang, S. Li, L. Zhu, J. Zou, X. Jiang, M. Chen, B. Chen

Published in: Clinical and Translational Oncology | Issue 8/2019

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Abstract

Purpose

Flap endonuclease 1 (FEN1) is up-regulated by estrogen (17β-estradiol, E2) and related to cisplatin resistance of human breast cancer cells. Letrozole, an aromatase inhibitor, suppresses the change of testosterone into estrogen and is frequently used to treat breast cancer. However, the effects of letrozole on FEN1 expression and cisplatin sensitivity in breast cancer cells overexpressing aromatase have not been revealed.

Methods

The expression of FEN1 and the proteins in ERK/Elk-1 signaling were evaluated by RT-PCR and Western blot. Cisplatin sensitivity was explored through CCK-8 and flow cytometry analysis, respectively. FEN1 siRNAs and FEN1 expression plasmid were transfected into cells to down-regulate or up-regulate FEN1 expression. The promotor activity of FEN1 was detected using luciferase reporter assay.

Results

FEN1 down-regulation improved cisplatin sensitivity of breast cancer cells overexpressing aromatase. Letrozole down-regulated FEN1 expression and increased cisplatin sensitivity. The sensitizing effect of letrozole to cisplatin was dependent on FEN1 down-regulation. FEN1 overexpression could block the sensitizing effect of letrozole to cisplatin. Testosterone up-regulated the promotor activity, protein expression of FEN1, and phosphorylation of ERK/Elk-1, which could be eliminated by both letrozole and MEK1/2 inhibitor U0126. Letrozole down-regulated FEN1 expression in an ERK/Elk-1-dependent manner.

Conclusions

Our findings clearly demonstrate that letrozole improves cisplatin sensitivity of breast cancer cells overexpressing aromatase via down-regulation of FEN1 and suggest that a combined use of letrozole and cisplatin may be a potential treatment protocol for relieving cisplatin resistance in human breast cancer.
Appendix
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Metadata
Title
Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1
Authors
Y. Wang
S. Li
L. Zhu
J. Zou
X. Jiang
M. Chen
B. Chen
Publication date
01-08-2019
Publisher
Springer International Publishing
Published in
Clinical and Translational Oncology / Issue 8/2019
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-018-02019-1

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