ERRα activates SHMT2 transcription to enhance the resistance of breast cancer to lapatinib via modulating the mitochondrial metabolic adaption.

Xin Li,Na Luo,Yu Hu,Kejing Zhang

doi:10.1042/bsr20192465

Xin Li, Na Luo + Show 2 more

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https://doi.org/10.1042/bsr20192465

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Journal: Bioscience reports	Publication Date: Jan 17, 2020
Citations: 19	License type: CC BY 4.0

Affiliation: Xiangya Hospital Central South University

Abstract

Lapatinib, a tyrosine kinase inhibitor, can initially benefit the patients with breast tumors but fails in later treatment due to the inevitable development of drug resistance. Estrogen-related receptor α (ERRα) modulates the metabolic adaptations in lapatinib-resistant cancer cells; however, the underlying mechanism remains unclear. ERRα was predicted to bind to the serine hydroxymethyltransferase 2 (SHMT2) transcription initiation site in the ER- and HER2-positive cell line BT-474; thus, we hypothesize that ERRα might modulate the resistance of breast cancer to lapatinib via regulating SHMT2. In the present study, we revealed that 2.5 and 5 µM lapatinib treatment could significantly decrease the expression and protein levels of ERRα and SHMT2; ERRα and SHMT2 expression and protein levels were significantly up-regulated in breast cancer cells, in particularly in breast cancer cells with resistance to lapatinib. ERRα knockdown restored the inhibitory effects of lapatinib on the BT-474R cell viability and migration; in the meantime, ERRα knockdown rescued the production of reactive oxygen species (ROS) whereas decreased the ratio of glutathione (GSH)/oxidized glutathione (GSSG) upon lapatinib treatment. Via targeting SHMT2 promoter region, ERRα activated the transcription of SHMT2. The effects of ERRα knockdown on BT-474R cells under lapatinib treatment could be significantly reversed by SHMT2 overexpression. In conclusion, ERRα knockdown suppresses the detoxification and the mitochondrial metabolic adaption in breast cancer resistant to lapatinib; ERRα activates SHMT2 transcription via targeting its promoter region, therefore enhancing breast cancer resistance to lapatinib.

Highlights

Breast cancer is one of the most common malignant tumors occurring on women throughout the world [1,2,3]
Estrogen-related receptor α (ERRα) and serine hydroxymethyltransferase 2 (SHMT2) expression could be up-regulated by lapatinib and is higher in lapatinib-resistant breast cancer cells
We revealed that 2.5 and 5 μM lapatinib treatment could significantly decrease the expression and protein levels of ERRα and SHMT2; ERRα and SHMT2 expression and protein levels were significantly up-regulated in breast cancer cells, in in breast cancer cells with resistance to lapatinib

Summary

Introduction

Breast cancer is one of the most common malignant tumors occurring on women throughout the world [1,2,3]. There are five subtypes of intrinsic breast cancer: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2 (HER2)-enriched and basal-like, each of which is unique in terms of incidence, survival and therapeutic response [4]. The receptor tyrosine kinase (RTK) signaling pathway overexpression and abnormal activation are essential in the development of human breast carcinoma [5,6]. As a dual epidermal growth factor receptor (EGFR)/human EGFR-2 (HER2) tyrosine kinase inhibitor (TKI), lapatinib is approved for use in patients with metastatic HER2-amplified breast tumors [7,8]. Lapatinib initially can benefit the patients with breast tumors, the inevitable development of drug resistance happens [9]

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