Abstract
Purpose
Paclitaxel, belongs to tubulin-binding agents (TBAs), shows a great efficacy against breast cancer via stabilizing microtubules. Drug resistance limits its clinical application. Here we aimed to explore a role of Polarity protein Par3 in improving paclitaxel effectiveness.
Methods
Breast cancer specimens from 45 patients were collected to study the relationship between Par3 expression and paclitaxel efficacy. The Kaplan–Meier method was used for survival analysis. Cell viability was measured in breast cancer cells (SK-BR-3 and T-47D) with Par3 over-expression or knockdown. The flow cytometry assays were performed to measure cell apoptosis and cell cycle. BrdU incorporation assay and Hoechst 33,258 staining were performed to measure cell proliferation and cell apoptosis, respectively. Immunofluorescence was used to detect microtubule structures.
Results
Par3 expression was associated with good response of paclitaxel in breast cancer patients. Consistently, Par3 over-expression significantly sensitized breast cancer cells to paclitaxel by promoting cell apoptosis and reducing cell proliferation. In Par3 overexpressing cells upon paclitaxel treatment, we observed intensified cell cycle arrests at metaphase. Further exploration showed that Par3 over-expression stabilized microtubules of breast cancer cells in response to paclitaxel and resists to microtubules instability induced by nocodazole, a microtubule-depolymerizing agent.
Conclusion
Par3 facilitates polymeric forms of tubulin and stabilizes microtubule structure, which aggravates paclitaxel-induced delay at the metaphase-anaphase transition, leading to proliferation inhibition and apoptosis of breast cancer cells. Par3 has a potential role in sensitizing breast cancer cells to paclitaxel, which may provide a more precise assessment of individual treatment and novel therapeutic targets.
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Data availability
The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.
Code availability
Not applicable.
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Funding
This work was supported by the National Natural Science Foundation (Grant Nos. 81772615, 81972294, 81772968) and Shanghai Anticancer Association (SACA-CY20B02).
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SC, YX and BW designed the study. YZ, HP, LL, YL, XH collected the clinical data, performed the experiments, created the figures and tables. YZ, YX and SC wrote and edited the manuscript.
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This study was approved by the research ethical committee of Fudan University Shanghai Cancer Center.
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Zhao, Y., Peng, H., Liang, L. et al. Polarity protein Par3 sensitizes breast cancer to paclitaxel by promoting cell cycle arrest. Breast Cancer Res Treat 192, 75–87 (2022). https://doi.org/10.1007/s10549-021-06490-3
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DOI: https://doi.org/10.1007/s10549-021-06490-3