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

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.

• Authors: Y Wang, S Li, L Zhu, J Zou, X Jiang, M Chen, B Chen
• Journal: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico (Clin Transl Oncol) Vol. 21 Issue 8 Pg. 1026-1033 (Aug 2019) ISSN: 1699-3055 [Electronic] Italy
• PMID: 30712236 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Aromatase Inhibitors
• Letrozole
• Aromatase
• CYP19A1 protein, human
• Flap Endonucleases
• FEN1 protein, human
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Aromatase (chemistry, metabolism)
• Aromatase Inhibitors (pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation
• Cisplatin (pharmacology)
• Down-Regulation
• Drug Resistance, Neoplasm (drug effects)
• Female
• Flap Endonucleases (antagonists & inhibitors, genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Letrozole (pharmacology)
• Signal Transduction
• Tumor Cells, Cultured