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Exploration of MELK as a downstream of Del-1 and druggable targets in triple-negative breast cancer

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Abstract

Purpose

In our previous study, Developmental endothelial locus-1 (Del-1) was a promising predictive marker for breast cancer. However, the downstream targets of Del-1 remain unknown. Here, we sought to discover a druggable target downstream of Del-1 and investigate the mechanism by which it regulates the course of breast cancer.

Methods

To investigate Del-1 downregulation effect on breast cancer, we performed transcriptome analysis using RNA sequencing of Del-1 knockdowned MDA-MB-231 cell line Plus, to investigate the expression of Del-1 and Maternal embryonic leucine zipper kinase (MELK), mRNA levels in eight different triple-Negative Breast Cancer (TNBC) cell lines were analyzed. High-throughput sequencing was performed on total RNA isolated. OTS167 was used for MELK inhibition. The effects of MELK on cell proliferation and invasion were determined using the MTT and Matrigel transwell assays. Furthermore, we examined MELK expression in breast cancer tissue.

Results

Del-1 and MELK mRNA expression levels were significantly higher in the TNBC cell lines, MDA-MB-468, HCC-1806, and MBA-MB-231. Knocking down Del-1 with siRNA in HCC-1806 and MBA-MB-231 cells significantly decreased MELK expression and thus suggested a possible relationship between Del-1 and MELK. In MDA-MB-468 cells, a basal-like 1 TNBC cell line, OTS167 significantly inhibited breast cancer cell proliferation and promoted cell apoptosis. To further investigate the relationship between Del-1 and MELK, dual inhibition of both Del-1 and MELK was performed, which significantly reduced the viability of MDA-MB-468 and MBA-MB-231 cells.

Conclusion

We found that MELK acts downstream of Del-1 and is a promising druggable target, especially in basal-like and mesenchymal stem-like subtype.

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Data availability

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.

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Funding

This work was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HR22C1832). This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2022R1I1A1A01070224). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (2022R1F1A1072458).

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Author notes

  1. In Hee Lee and Soo Jung Lee are equally contributed to this paper.

Authors and Affiliations

  1. Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicien, Kyungpook National University, Daegu, Republic of Korea

    In Hee Lee, Soo Jung Lee & Yee Soo Chae

  2. Breast & Thyroid Surgery, Kyungpook National University Chilgok Hospital, School of Medicien, Kyungpook National University, Daegu, Republic of Korea

    Byeongju Kang, Jeeyeon Lee, Jin Hyang Jung & Ho Yong Park

  3. Department of Pathology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

    Ji-Young Park & Nora Jee-Young Park

  4. Cell & Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea

    Eun Ae Kim

  5. Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea

    Jieun Kang

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  1. In Hee Lee
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Contributions

YSC and SJL contributed to the study conception and design. Material preparation and data collection were performed by BK, JL and JHJ, JYP, NJYP, and HYP. The analysis was performed by IHL, EAK and JK. The first draft of the manuscript was written by IHL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yee Soo Chae.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The study was conducted according to the guidelines of the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments. This study was approved by the Institutional Review Board of KNUCH (KNUCH 2020-0-025). Written informed consent was obtained from all individual participants included in the study.

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Informed consent was obtained from all individual participants included in the study.

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Lee, I.H., Lee, S.J., Kang, B. et al. Exploration of MELK as a downstream of Del-1 and druggable targets in triple-negative breast cancer. Breast Cancer Res Treat 205, 181–191 (2024). https://doi.org/10.1007/s10549-023-07198-2

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  • DOI: https://doi.org/10.1007/s10549-023-07198-2

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