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Wnt3a/GSK3β/β-catenin Signalling Modulates Doxorubicin-associated Memory Deficits in Breast Cancer

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Abstract

Background: Chemobrain is widespread in breast cancer patients receiving chemotherapy. However, the exact mechanism, especially the associated signalling pathway, is not currently clear. This study was to evaluate the behavioural changes in breast cancer mice after chemotherapy and to further explore the role of Wnt3a/glycogen synthase kinase (GSK3β)/β-catenin signalling in chemobrain. Methods: MMTV-PyMT(+) breast cancer mice were injected intraperitoneally with doxorubicin (4 mg/kg) once a week for three weeks to establish a chemobrain model. The Morris water maze (MWM) and novel object recognition (NOR) tests were performed to assess the learning and memory ability. Electron microscopy was used to observe the structural changes in the hippocampal CA1 region. The brain tissue of breast cancer mice after chemotherapy was taken out for mRNA-seq detection. Then, the expression levels and phosphorylation of key proteins in the Wnt3a/GSK3 β/β-catenin signalling pathway were evaluated through Western blotting (WB) and immunofluorescence. Results: Doxorubicin-induced spatial and short-term memory impairment was observed in breast cancer mice, and obvious neuronal damage could be seen in the hippocampal CA1 region. Immunofluorescence staining for GSK3β was increased. Wnt signalling pathway is highly enriched from mRNA-seq analysis, with GSK3β genes at important nodes. The relative protein levels of p-PI3K, p-AKT, p-GSK3 β, Wnt3a and TCF-1 were decreased significantly, while the p-β-catenin level was increased. After injection of the GSK3β inhibitor sb216763 (1 ng/0.5 µl/side), hippocampal neuronal injury was alleviated to some extent, and the changes in the expression of proteins upstream and downstream of this signalling pathway were reversed. Conclusion: Wnt3a/GSK3 β/β-catenin signalling is likely involved in doxorubicin-induced memory impairment. This result provides basic evidence for the further study of chemobrain in breast cancer.

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Funding

This research was supported by the National Natural Science Foundation of China (No. 81872504).

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  1. Wen Li, Chen Gan and Sheng Yu contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, China

    Wen Li, Chen Gan, Sheng Yu, Jian Xu & LingXue Tang

  2. The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510500, China

    Huaidong Cheng

  3. Department of Oncology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518000, China

    Wen Li, Chen Gan, Sheng Yu, Jian Xu, LingXue Tang & Huaidong Cheng

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Contributions

Wen Li constructed the model, performed the behavioural tests, conducted the experiments, and wrote the manuscript; Chen Gan, and Sheng Yu performed data collection; Jian Xu arranged the manuscript; Lingxue Tang performed statistical analysis; Huaidong Cheng designed the project. All authors contributed to manuscript editing.

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Correspondence to Huaidong Cheng.

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Li, W., Gan, C., Yu, S. et al. Wnt3a/GSK3β/β-catenin Signalling Modulates Doxorubicin-associated Memory Deficits in Breast Cancer. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-023-03910-x

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  • DOI: https://doi.org/10.1007/s12035-023-03910-x

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