HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer
Ellen C. de Heer,1 Mathilde Jalving,1 and Adrian L. Harris2
1University of Groningen, University Medical Center Groningen, Department of Medical Oncology, Groningen, Netherlands.
2Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Address correspondence to: Adrian L. Harris, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS United Kingdom. Email: adrian.harris@oncology.ox.ac.uk.
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1University of Groningen, University Medical Center Groningen, Department of Medical Oncology, Groningen, Netherlands.
2Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Address correspondence to: Adrian L. Harris, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS United Kingdom. Email: adrian.harris@oncology.ox.ac.uk.
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1University of Groningen, University Medical Center Groningen, Department of Medical Oncology, Groningen, Netherlands.
2Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Address correspondence to: Adrian L. Harris, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS United Kingdom. Email: adrian.harris@oncology.ox.ac.uk.
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First published September 1, 2020 - More info
J Clin Invest. 2020;130(10):5074–5087. https://doi.org/10.1172/JCI137552.
© 2020 American Society for Clinical Investigation
Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing of escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in patients with breast cancer. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment.
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