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Combination of monensin and erlotinib synergistically inhibited the growth and cancer stem cell properties of triple-negative breast cancer by simultaneously inhibiting EGFR and PI3K signaling pathways

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Abstract

Background

Cancer stem cells (CSCs) in triple-negative breast cancer (TNBC) are recognized as a highly challenging subset of cells, renowned for their heightened propensity for relapse and unfavorable prognosis. Monensin, an ionophoric antibiotic, has been reported to exhibit significant therapeutic efficacy against various cancers, especially CSCs. Erlotinib is classified as one of the EGFR-TKIs and has been previously identified as a promising therapeutic target for TNBC. Our research aims to assess the effectiveness of combination of monensin and erlotinib as a potential treatment strategy for TNBC.

Methods

The combination of monensin and erlotinib was assessed for its potential anticancer activity through various in vitro assays, including cytotoxicity assay, colony formation assay, wound healing assay, transwell assay, mammosphere formation assay, and proportion of CSCs assay. Additionally, an in vivo study using tumor-bearing nude mice was conducted to evaluate the inhibitory effect of the monensin and erlotinib combination on tumor growth.

Results

The results indicated that combination of monensin with erlotinib synergistically inhibited cell proliferation, the migration rate, the invasion ability and decreased the CSCs proportion, and CSC markers SOX2 and CD133 in vivo and in vitro. Furthermore, the primary proteins involved in the signaling pathways of the EGFR/ERK and PI3K/AKT are simultaneously inhibited by the combination treatment of monensin and erlotinib in vivo and in vitro.

Conclusions

The simultaneous inhibition of the EGFR/ERK and PI3K/AKT/mTOR signaling pathways by the combination of monensin and erlotinib exhibited a synergistic effect on suppressing tumor proliferation and cancer cell stemness in TNBC.

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Data availability

The datasets of this study are available on request to the corresponding author.

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Funding

This work was supported by the grants from the National Natural Science Foundation of China (32172918&31902326), the Fundamental Research Funds for the Central Universities (KYGD202002), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Authors and Affiliations

  1. Engineering Center of Innovativennovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, Nan**g Agricultural University, 1 Weigang, Nan**g, 210095, China

    Tian Fang, Shiheng Hu, **nhao Song, Junqi Wang, Runan Zuo, Shanxiang Jiang & Dawei Guo

  2. MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nan**g Agricultural University, 1 Weigang, Nan**g, 210095, China

    Tian Fang, Shiheng Hu, **nhao Song, Junqi Wang, Runan Zuo, Shanxiang Jiang & Dawei Guo

  3. Department of Comparative Medicine, Affiliated Hospital of Medicine School, Nan**g **ling Hospital, Nan**g University, Nan**g, 210002, China

    Tian Fang & Shifeng Yun

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  1. Tian Fang
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  2. Shiheng Hu
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  3. **nhao Song
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  4. Junqi Wang
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  7. Shanxiang Jiang
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Contributions

TF: supervised and designed the research, provided expertise to the bioinformatics and laboratory concepts, and wrote the paper. SH: assisted with the cytotoxicity assays and WB studies, analyzed and interpreted the data. XS: assisted with the colony formation assay and cell apoptosis assay, wrote the paper. JW: assisted with wound healing assay, transwell assay, and mammosphere formation assay. RZ: assisted with animal experiment. SY: assisted with IHC. SJ: supervised and designed the research. DG: wrote the main manuscript text. All authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Shanxiang Jiang or Dawei Guo.

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Fang, T., Hu, S., Song, X. et al. Combination of monensin and erlotinib synergistically inhibited the growth and cancer stem cell properties of triple-negative breast cancer by simultaneously inhibiting EGFR and PI3K signaling pathways. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07374-y

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