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Comparative stemness and differentiation of luminal and basal breast cancer stem cell type under glutamine‐deprivation

Journal of Cell Communication and Signaling volume 15, pages 207–222 (2021)Cite this article

Abstract

Glutamine (gln) metabolism has emerged as a cancer therapeutic target in past few years, however, the effect of gln-deprivation of bCSCs remains elusive in breast cancer. In this study, effect of glutamine on stemness and differentiation potential of bCSCs isolated from MCF-7 and MDAMB-231 were studied. We have shown that bCSCs differentiate into CD24+ epithelial population under gln-deprivation and demonstrated increased expression of epithelial markers such as e-cadherin, claudin-1 and decreased expression of mesenchymal protein n-cadherin. MCF-7-bCSCs showed a decrease in EpCAMhigh population whereas MDAMB-231-bCSCs increased CD44high population in response to gln-deprivation. The expression of intracellular stem cell markers such sox-2, oct-4 and nanog showed a drastic decrease in gene expression under gln-deprived MDAMB-231-bCSCs. Finally, localization of β-catenin in MCF-7 and MDAMB-231 cells showed its accumulation in cytosol or perinuclear space reducing its efficiency to transcribe downstream genes. Conclusively, our study demonstrated that gln-deprivation induces differentiation of bCSCs into epithelial subtypes and also reduces stemness of bCSCs mediated by reduced nuclear localization of β-catenin. It also suggests that basal and luminal bCSCs respond differentially towards changes in extracellular and intracellular gln. This study could significantly affect the gln targeting regimen of breast cancer therapeutics.

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Acknowledgements

Mrs. Monika Seervi for their technical support for flow cytometry experiments.

Funding

National Institute of Pharmaceuticals Education and Research-Ahmedabad, Department of Pharmaceutics, Ministry of Chemicals and Fertilizers, Government of India. DST-SERB Grant (ECR/2016/002038), DBT supported Ramalingaswami Grant (BT/HRD/35/02/2006).

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Authors and Affiliations

  1. Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat, India

    Heena Jariyal, Chanchal Gupta, Shambhavi Andhale & Sonali Gadge

  2. Department of Medical Devices, National Institute of Pharmaceutical Education and Research-Ahmedabad, Opposite Air force Station, Palaj, Gandhinagar, Gujarat, 382355, India

    Akshay Srivastava

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  1. Heena Jariyal
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Contributions

H.J. and A.S. designed the manuscript. H.J., C.G., S.A. S.G. performed the experiments. H.J. and A.S analysed the data. H.J, drafted the manuscript and A.S. edited the manuscript. All authors have read and approved the manuscript.

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Correspondence to Akshay Srivastava.

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Jariyal, H., Gupta, C., Andhale, S. et al. Comparative stemness and differentiation of luminal and basal breast cancer stem cell type under glutamine‐deprivation. J. Cell Commun. Signal. 15, 207–222 (2021). https://doi.org/10.1007/s12079-020-00603-1

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Keywords

  • Breast cancer stem cells
  • Glutamine
  • 2‐Diazo‐norleucine (DON)
  • Epithelial mesenchymal transition
  • β-Catenin