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Study on the Mechanism of Post-Chemotherapy Metastasis in Breast Cancer Based on Metabolomics and Development of TCM
Zhe Yu1, Weiqi Wang1, Junjie Tao2
1College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, Jilin, China.
Introduction:
Breast cancer (BC) is a leading global malignancy in women. Although central to treatment, chemotherapy may paradoxically promote metastasis. The role of metabolic changes in chemotherapy- induced metastasis remains unclear. This study aims to investigate the association between metabolic alterations and BC metastasis after CMF (cyclophosphamide (CCP), methotrexate (MTX), and 5-fluorouracil (5-FU)) chemotherapy.
Methods:
A murine BC model treated with CMF was used. Metabolomic profiling identified altered pathways. Metastasis was assessed via tumor growth, hematoxylin and eosin (H&E), and immunohistochemistry (IHC). Phospholipid metabolism was inhibited with idelalisib combined with CMF. Traditional Chinese medicine (TCM) components were screened. Epicatechin (EC) was identified as a modulator of phospholipid metabolism and tested in CMF.
Results:
Metabolomic analysis revealed a marked upregulation of phospholipid metabolism in CMF-treated BC mice, which was linked to enhanced metastasis. Intervening with idelalisib in combination with CMF abolished these protumorigenic effects. Among the screened TCM components, EC was identified as a modulator of phospholipid metabolism. Similarly, the combination of EC and CMF maintained chemotherapy's antitumor efficacy while substantially reducing metastatic spread.
Discussion:
Our findings reveal that CMF chemotherapy induces phospholipid metabolic reprogramming, which drives BC metastasis. Targeting this pathway-either through pharmacological inhibitors (idelalisib) or natural compounds (EC)-can mitigate chemotherapy-induced metastasis without compromising tumor suppression. This suggests that metabolic modulation could be a viable strategy to enhance chemotherapy efficacy.
Conclusion:
Upregulated phospholipid metabolism is a critical mechanism behind chemotherapy-induced BC metastasis. Combining CMF with phospholipid-targeting agents (idelalisib or EC) offers a promising therapeutic approach to optimize chemotherapy outcomes. These results provide a theoretical foundation for developing novel combination therapies in BC treatment.
