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Serotonin 5-HT7 receptor is a biomarker poor prognostic factor and induces proliferation of triple-negative breast cancer cells through FOXM1

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Abstract

Background

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and associated with poor prognosis and shorter survival due to significant genetic heterogeneity, drug resistance and lack of effective targeted therapeutics. Therefore, novel molecular targets and therapeutic strategies are needed to improve patient survival. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to induce growth stimulatory effects in breast cancer. However, the molecular mechanisms by which 5-HT exerts its oncogenic effects in TNBC still are not well understood.

Methods

Normal breast epithelium (MCF10A) and two TNBC cells (MDA-MB-231, BT-546) and MCF-7 cells (ER +) were used to investigate effects of 5-HT7 receptor. Small interfering RNA (siRNA)-based knockdown and metergoline (5-HT7 antagonist) were used to inhibit the activity of 5-HT7. Cell proliferation and colony formation were evaluated using MTS cell viability and colony formation assays, respectively. Western blotting was used to investigate 5-HT7, FOXM1 and its downstream targets protein expressions.

Results

We demonstrated that 5-HT induces cell proliferation of TNBC cells and expression of 5-HT7 receptor and FOXM1 oncogenic transcription factor. We found that expression of 5-HT7 receptor is up-regulated in TNBC cells and higher 5-HT7 receptor expression is associated with poor patient prognosis and shorter patient survival. Genetic and pharmacological inhibition of 5-HT7 receptor by siRNA and metergoline, respectively, suppressed TNBC cell proliferation and FOXM1 and its downstream mediators, including eEF2-Kinase (eEF2K) and cyclin-D1.

Conclusion

Our findings suggest for the first time that the 5-HT7 receptor promotes FOXM1, eEF2K and cyclin D1 signaling to support TNBC cell proliferation; thus, inhibition of 5-HT7 receptor/FOXM1 signaling may be used as a potential therapeutic strategy for targeting TNBC.

Graphical abstract

5-HT induces cell proliferation of TNBC cells through 5-HT7 receptor signaling. Also, genetic and pharmacological inhibition of 5-HT7 by RNAi (siRNA) and metergoline HTR7 antagonist, respectively inhibits FOXM1 oncogenic transcription factor and suppresses TNBC cell proliferation.

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Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was supported by Erciyes University Research Fund (Project Number: TYL-2019-9187).

Funding

This study was supported by Erciyes University Research Fund (Project Number: TYL-2019–9187).

Author information

Authors and Affiliations

  1. Faculty of Medicine, Department of Medical Biology, Erciyes University, Kayseri, Turkey

    Venhar Cınar, Zuhal Hamurcu, Ahsen Guler & Nursultan Nurdinov

  2. Betül-Ziya Eren Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey

    Venhar Cınar, Zuhal Hamurcu, Ahsen Guler & Nursultan Nurdinov

  3. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, 77030, USA

    Zuhal Hamurcu & Bulent Ozpolat

  4. RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Bulent Ozpolat

  5. Houston Methodist Neal Cancer, Houston, TX, USA

    Bulent Ozpolat

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  1. Venhar Cınar
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Contributions

All authors analyzed the results and approved the final version of the manuscript. Zuhal Hamurcu conceptualized, coordinated, administered the study, performed experiments, and wrote the paper. Bulent Ozpolat conceived, conceptualized, supervised the study, and revised and edited the manuscript. Venhar Cınar, Ahsen Guler, and Nursultan Nurdınov helped performing the experiments. All authors read and approved the final manuscript.

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Correspondence to Bulent Ozpolat.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, and approved the final version of the manuscript being submitted. The results presented in this paper have not been published previously in whole or part.

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Cınar, V., Hamurcu, Z., Guler, A. et al. Serotonin 5-HT7 receptor is a biomarker poor prognostic factor and induces proliferation of triple-negative breast cancer cells through FOXM1. Breast Cancer 29, 1106–1120 (2022). https://doi.org/10.1007/s12282-022-01391-9

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  • DOI: https://doi.org/10.1007/s12282-022-01391-9

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