Translational Therapeutics

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

Abstract

Background

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. However, its underlying molecular mechanism remains unclear.

Methods

Clinical 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.

Results

The 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.

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.

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Fig. 1: Calcification is associated with adverse clinical prognostic factors in patients with breast cancer.
Fig. 2: Detection of calcification in vitro.
Fig. 3: Enhancement of metastatic ability and activation of epithelial-to-mesenchymal transition (EMT)-related signalling pathways in breast cancer cells after osteogenic induction.
Fig. 4: Minor alterations in glycolysis metabolism of breast cancer cells during osteogenic differentiation.
Fig. 5: Enhancement of mitochondrial metabolism in the calcification-mediated epithelial-to-mesenchymal transition (EMT) model.
Fig. 6: Alteration of OXPHOS activity is associated with aggressive cancer phenotypes in breast cancer cells during osteogenic differentiation.

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Acknowledgements

We thank all the members of the laboratory for their help in discussions and for providing technical assistance.

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Authors

Contributions

D.Z., W.C. and G.Q. designed the research. Y.H. and W.X. performed the experiment. Y.H., W.X., Z.H., H.Z. and X.L. analysed the data; Y.H. prepared the original draft. D.Z., W.C. and G.Q. reviewed and edited the paper.

Corresponding authors

Correspondence to Genggeng Qin or Weiguo Chen.

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This study was reviewed and approved by the ethics committee of Nanfang Hospital, Southern Medical University. Informed consent was obtained from all participants (reference number: NFEC-201706-K3-01). The study was conducted in accordance with the Declaration of Helsinki.

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All data generated or analysed during this study are included in this paper.

Competing interests

The authors declare no competing interests.

Funding information

This research was supported by the National Key Research and Development Program of China (grant numbers “2019YFC0117301” and “2019YFC0121903”), Natural Science Foundation of Guangdong Province (grant number “2019A1515011168”) and Medical Research Fund of Guangdong Province (grant number “A2017496”).

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Hu, Y., Xu, W., Zeng, H. et al. OXPHOS-dependent metabolic reprogramming prompts metastatic potential of breast cancer cells under osteogenic differentiation. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-01040-y

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