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Effects of thiostrepton alone or in combination with selumetinib on triple-negative breast cancer metastasis

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Abstract

Objective

FoxM1 transcription factor contributes to tumor metastasis and poor prognosis in many cancers including triple-negative breast cancer (TNBC). In this study, we examined the effects of FoxM1 inhibitor Thiostrepton (THIO) alone or in combination with MEK inhibitor Selumetinib (SEL) on metastatic parameters in vitro and in vivo.

Methods

Cell viability was determined by MTT assay. Immunoblotting and immunohistochemistry was used to assess metastasis-related protein expressions in 4T1 cells and its allograft tumor model in BALB/c mice. In vivo uPA activity was determined by enzymatic methods.

Results

Both inhibitors were effective on the expressions of FoxM1, ERK, p-ERK, Twist, E-cadherin, and Vimentin alone or in combination in vitro. THIO significantly decreased 4T1 cell migration and changed the cell morphology from mesenchymal-like to epithelial-like structure. THIO was more effective than in combination with SEL in terms of metastatic protein expressions in vivo. THIO alone significantly inhibited mean tumor growth, decreased lung metastasis rate and tumor foci, however, no significant changes in these parameters were observed in the combined group. Immunohistochemically, FoxM1 expression intensity was decreased with THIO and its combination with SEL in the tumors.

Conclusions

This study suggests that inhibiting FoxM1 as a single target is more effective than combined treatment with MEK in theTNBC allograft model. The therapeutic efficacy of THIO should be investigated with further studies on appropriate drug delivery systems.

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Acknowledgements

We thank to Dr. Gunes Esendagli for his valuable contributions to this study, Dr. Digdem Yoyen Ermis for assistance animal studies and Ilknur Gunduz for preparing pathological samples.

Funding

This work was supported by the Scientific and Technological Research Council of Turkey, (TUBITAK) under Grant (number 1002-116S162) and Teaching Staff Training Program of Turkey.

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Authors and Affiliations

  1. Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Ankara, Turkey

    Funda Demirtas Korkmaz & Abdullah Ekmekci

  2. Department of Medical Biology, Faculty of Medicine, Giresun University, Giresun, 28100, Turkey

    Funda Demirtas Korkmaz

  3. Department of Medical Biology, Faculty of Medicine, Ufuk University, Ankara, Turkey

    Irem Dogan Turacli

  4. Department of Medical Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey

    Guldal Esendagli

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  1. Funda Demirtas Korkmaz
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Contributions

FDK, IDT, AE participated in the design, interpretation of the studies and analysis of the data and review of the manuscript; FDK and GE conducted the experiments, FDK wrote the manuscript, and IDT, AE edited the manuscript.

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Correspondence to Funda Demirtas Korkmaz.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants.

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Demirtas Korkmaz, F., Dogan Turacli, I., Esendagli, G. et al. Effects of thiostrepton alone or in combination with selumetinib on triple-negative breast cancer metastasis. Mol Biol Rep 49, 10387–10397 (2022). https://doi.org/10.1007/s11033-022-07751-0

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