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Open AccessArticle

Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells

1
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
2
Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
3
Department of Basic Science, Kansas City University of Medicine and Bioscience, 1750 Independence Ave, Kansas City, MO 64106, USA
4
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
5
Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Sir Frederick G. Banting Research Centre, 251 Sir Frederick Banting Driveway, Ottawa, ON K1A 0K9, Canada
6
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Int. J. Mol. Sci. 2020, 21(16), 5788; https://doi.org/10.3390/ijms21165788
Received: 21 July 2020 / Revised: 6 August 2020 / Accepted: 10 August 2020 / Published: 12 August 2020
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapeutic Approaches)
Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet medical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with hypoxia that, in turn, promotes cancer stem cell (CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased cisplatin efficacy in the clinic for the treatment of TNBC. In this report we analyzed clinical datasets of TNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression. A similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We, thus, developed a new therapeutic approach to inhibit EGFR and hypoxia by combination treatment with metformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both CD44+/CD24− and ALDH+ CSCs. We demonstrated a similar inhibition efficacy on organotypic cultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in the clinic; this study illustrates a novel, clinically translatable therapeutic approach to treat patients with TNBC. View Full-Text
Keywords: triple negative breast cancer; cancer stem cell; hypoxia; EGFR; cisplatin; PDX triple negative breast cancer; cancer stem cell; hypoxia; EGFR; cisplatin; PDX
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MDPI and ACS Style

Sulaiman, A.; McGarry, S.; Chambers, J.; Al-Kadi, E.; Phan, A.; Li, L.; Mediratta, K.; Dimitroulakos, J.; Addison, C.; Li, X.; Wang, L. Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells. Int. J. Mol. Sci. 2020, 21, 5788.

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