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FOXM1 mediates GDF-15 dependent stemness and intrinsic drug resistance in breast cancer

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Abstract

Background

Stemness, a key component of breast cancer (BC) heterogeneity, is responsible for chemoresistance. Growth differentiation factor-15 (GDF-15) induces drug resistance and stemness in BC cells. In this study, the expressions and interactions of GDF-15, FOXM1, and stemness (OCT4 and SOX2), and drug resistance (ABCC5) markers were evaluated in BC.

Methods and results

40 diagnosed BC patients and 40 healthy controls were included in this study. Serum GDF-15 was significantly raised (p < 0.001) in BC patients. Expressions of GDF-15, OCT4, SOX2, and FOXM1 in BC tissue and cell lines (MCF-7 and MDA-MB-231) were determined by RT-PCR, while phosphorylated AKT (p-AKT) was analyzed by Western blot. Not only were the fold change expressions higher in cancer tissue as compared to surrounding control tissue, but a higher expression was observed for all the genes along with p-AKT in MDA-MB-231 cells compared to MCF-7. Tissue GDF-15 was significantly associated with ABCC5 (p < 0.001), OCT4 (p = 0.002), SOX2 (p < 0.001), and FOXM1 (p < 0.001). To further analyze the signaling pathway involved in stemness and drug resistance in BC, GDF-15 knockdown was performed, which reduced the expression of p-AKT, FOXM1, OCT4 and SOX2, and ABCC5, whereas recombinant GDF-15 treatment reversed the same. In silico analyses in UALCAN revealed a similar picture for these genes to that of BC tissue expression.

Conclusions

GDF-15 promotes stemness and intrinsic drug resistance in BC, possibly mediated by the p-AKT/FOXM1 axis.

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Data availability

The data related to this article can be accessed by contacting the corresponding author.

Abbreviations

ABC:

ATP-binding cassette

BC:

Breast cancer

BCSC:

Breast cancer stem cells

CSC:

Cancer stem cells

ER:

Estrogen receptor

FOXM1:

Forkhead box M1

GDF-15:

Growth Differentiation Factor-15

HER2:

Human epidermal growth factor receptor

OCT4:

Octamer-binding transcription factor 4

PR:

Progesterone receptor

SOX2:

Sex determining region Y-box 2

TGF-β:

Transforming growth factor-β

TNBC:

Triple negative breast cancer

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Funding

This work was supported by the Intramural Funding of AIIMS, Jodhpur under Grant Number (AIIMS/RES/2019/3056) and Department of Biotechnology, Ministry of Science and Technology under Grant Number (DBT/2018/AIIMS-J/994).

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Authors and Affiliations

  1. Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Jodhpur, Rajasthan, India

    Anupama Modi, Purvi Purohit, Dipayan Roy, Shailja Sharma & Praveen Sharma

  2. Department of Surgical Oncology, All India Institute of Medical Sciences (AIIMS), Jodhpur, Rajasthan, India

    Jeewan Ram Vishnoi & Sanjeev Misra

  3. Department of Radiotherapy, All India Institute of Medical Sciences (AIIMS), Jodhpur, Rajasthan, India

    Puneet Pareek

  4. Department of Pathology and Lab Medicine, All India Institute of Medical Sciences (AIIMS), Jodhpur, Rajasthan, India

    Poonam Elhence

  5. Department of Bioscience and Bioengineering, Indian Institute of Technology (IIT), Jodhpur, Rajasthan, India

    Priyanka Singh

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  1. Anupama Modi
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  2. Purvi Purohit
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  3. Dipayan Roy
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Contributions

Conception, organization and execution: AM, PP1; Data collection and analysis: AM, PP1, DR; Manuscript drafting: AM, PP1, DR; Data visualization: AM, DR; Review and critique of the manuscript: PP1, JRV, PP2, PE, PS1, SS, PS2, SM; Supervision of the project: PP1; All authors agreed to the final version of the manuscript.

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Correspondence to Purvi Purohit.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Modi, A., Purohit, P., Roy, D. et al. FOXM1 mediates GDF-15 dependent stemness and intrinsic drug resistance in breast cancer. Mol Biol Rep 49, 2877–2888 (2022). https://doi.org/10.1007/s11033-021-07102-5

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