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Hyperglycemic conditions proliferate triple negative breast cancer cells: role of ornithine decarboxylase

  • Preclinical study
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Abstract

Purpose

Several cancer subtypes (pancreatic, breast, liver, and colorectal) rapidly advance to higher aggressive stages in diabetes. Though hyperglycemia has been considered as a fuel for growth of cancer cells, pathways leading to this condition are still under investigation. Cellular polyamines can modulate normal and cancer cell growth, and inhibitors of polyamine synthesis have been approved for treating colon cancer, however the role of polyamines in diabetes-mediated cancer advancement is unclear as yet. We hypothesized that polyamine metabolic pathway is involved with increased proliferation of breast cancer cells under high glucose (HG) conditions.

Methods

Studies were performed with varying concentrations of glucose (5–25 mM) exposure in invasive, triple negative breast cancer cells, MDA-MB-231; non-invasive, estrogen/progesterone receptor positive breast cancer cells, MCF-7; and non-tumorigenic mammary epithelial cells, MCF-10A.

Results

There was a significant increase in proliferation with HG (25 mM) at 48–72 h in both MDA-MB-231 and MCF-10A cells but no such effect was observed in MCF-7 cells. This was correlated to higher activity of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine synthesis pathway. Inhibitor of polyamine synthesis (difluoromethylornithine, DFMO, 5 mM) was quite effective in suppressing HG-mediated cell proliferation and ODC activity in MDA-MB-231 and MCF-10A cells. Polyamine (putrescine) levels were significantly elevated with HG treatment in MDA-MB-231 cells. HG exposure also increased the metastasis of MDA-MB-231 cells.

Conclusions

Our cellular findings indicate that polyamine inhibition should be explored in patient population as a target for future chemotherapeutics in diabetic breast cancer.

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Data availability

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

Research reported in this publication was supported by NIH Grants: GM103427 (SC), CA204345 (RAC), and CA235863 (RAC). In addition, funding was received from Nebraska Research Initiative Collaborative Seed Grant (SC), and Samuel Waxman Cancer Research Foundation (RAC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Cell culture facility and fluorescence microscopy facilities at UNK were supported by grants from the National Institute for General Medical Science (NIGMS) (5P20GM103427), a component of the National Institutes of Health (NIH), as well as Nebraska Research Initiative. HT was supported as graduate research assistant through financial support provided by the Division of Research and the Office of Graduate Studies and Academic Outreach at University of Nebraska at Kearney.

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Authors and Affiliations

  1. Department of Biology, University of Nebraska-Kearney, 2401 W. 11th Ave, BHS335, Kearney, NE, 68849, USA

    Caleb C. Capellen, Jose Ortega-Rodas, M. Jane Morwitzer, Hadassha M. N. Tofilau & Surabhi Chandra

  2. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    M. Jane Morwitzer

  3. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Bunting/Blaustein Cancer Research Building 1 1650 Orleans Street - Room 551, Baltimore, MD, 21231, USA

    Matthew Dunworth & Robert A. Casero Jr.

Authors
  1. Caleb C. Capellen
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  2. Jose Ortega-Rodas
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  3. M. Jane Morwitzer
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  6. Robert A. Casero Jr.
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  7. Surabhi Chandra
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Contributions

CC, the primary author was involved with project design, experimentation, and writing the manuscript; JO and JM performed cellular assays; MD under the supervision of RAC performed enzyme activity assays at John Hopkins; HT edited the manuscript; and SC and RAC supervised the work, helped with project design, and edited the manuscript. We thank Dr Sophie Alvarez at the Proteomics & Metabolomics Facility, Nebraska Center for Biotechnology at the University of Nebraska-Lincoln for the polyamines analysis. The facility and instrumentation are supported by the Nebraska Research Initiative.

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Correspondence to Surabhi Chandra.

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Capellen, C.C., Ortega-Rodas, J., Morwitzer, M.J. et al. Hyperglycemic conditions proliferate triple negative breast cancer cells: role of ornithine decarboxylase. Breast Cancer Res Treat 190, 255–264 (2021). https://doi.org/10.1007/s10549-021-06388-0

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  • DOI: https://doi.org/10.1007/s10549-021-06388-0

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