OXPHOS-dependent metabolic reprogramming prompts metastatic potential of breast cancer cells under osteogenic differentiation

Yangling Hu,Weimin Xu,Genggeng Qin,Xiao Lu,Hui Zeng,Weiguo Chen,Zilong He,Daming Zuo

doi:10.1038/s41416-020-01040-y

Yangling Hu, Weimin Xu + Show 6 more

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https://doi.org/10.1038/s41416-020-01040-y

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Abstract

BackgroundMicrocalcification is one of the most reliable clinical features of the malignancy risk of breast cancer, and it is associated with enhanced tumour aggressiveness and poor prognosis. However, its underlying molecular mechanism remains unclear.MethodsClinical data were retrieved to analyse the association between calcification and bone metastasis in patients with breast cancer. Using multiple human breast cancer cell lines, the osteogenic cocktail model was established in vitro to demonstrate calcification-exacerbated metastasis. Migration and invasion characteristics were determined by wound healing and transwell migration. mRNA and protein expression were identified by quantitative PCR and western blotting. Metabolic alterations in breast cancer cells were evaluated using Seahorse Analyser.ResultsThe osteogenic differentiation of human breast cancer cells activated the classical TGF-β/Smad signalling pathway and the non-canonical MAPK pathway, which, in turn, exacerbated the progression of epithelial–mesenchymal transition (EMT). The metabolic programme switched to enhancing mitochondrial oxidative phosphorylation (OXPHOS) upon osteogenic differentiation. Rotenone was used to inhibit the OXPHOS complex during osteogenesis to block mitochondrial function, consequently reversing the EMT phenotype.ConclusionsThis study provides important insights into the mechanisms involved in breast cancer bone metastasis, and outlines a possible strategy to intervene in OXPHOS for the treatment of breast tumours.

Highlights

Microcalcification is one of the most reliable clinical features of the malignancy risk of breast cancer, and it is associated with enhanced tumour aggressiveness and poor prognosis
Our study describes the molecular mechanism that underlies the association of the formation of calcification in breast cancer with its metastatic capacity
epithelial–mesenchymal transition (EMT) was strongly induced in breast cancer cells upon osteogenic differentiation

Summary

Introduction

Microcalcification is one of the most reliable clinical features of the malignancy risk of breast cancer, and it is associated with enhanced tumour aggressiveness and poor prognosis. CONCLUSIONS: This study provides important insights into the mechanisms involved in breast cancer bone metastasis, and outlines a possible strategy to intervene in OXPHOS for the treatment of breast tumours. Calcium oxalate is mostly associated with benign lesions, whereas HA is related to both benign and malignant breast tumours.[6] Calcifications represent one of the most reliable clinical signs of malignancy in breast cancer, and previous studies have revealed that HA potentially enhances breast tumour progression and malignancy. The determination of the molecular mechanisms of calcification formation and evaluation of its clinical significance in the development of breast cancer are important

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