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HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer
Ellen C. de Heer, … , Mathilde Jalving, Adrian L. Harris
Ellen C. de Heer, … , Mathilde Jalving, Adrian L. Harris
Published September 1, 2020
Citation Information: J Clin Invest. 2020;130(10):5074-5087. https://doi.org/10.1172/JCI137552.
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Review Series

HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer

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Abstract

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.

Authors

Ellen C. de Heer, Mathilde Jalving, Adrian L. Harris

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Figure 1

Schematic overview of HIFs and HIF-induced angiogenesis in breast cancer.

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Schematic overview of HIFs and HIF-induced angiogenesis in breast cancer...
HIF is stimulated by both hypoxia and O2-independent oncogenic, metabolic, and therapeutic factors. HIF drives angiogenesis by inducing secretion of proangiogenic growth factors by tumor cells and stromal cells, such as adipocytes and fibroblasts. The newly formed vasculature is disorganized and leaky, which facilitates tumor cell invasion and metastasis, impairs drug delivery, and further aggravates hypoxia in the tumor and the microenvironment. Angiogenic growth factors also contribute to an immunosuppressive tumor microenvironment, particularly by increasing recruitment of immunosuppressive cells. Compounds targeting angiogenic key players are listed in pink text. The key indicates their furthest stage of development in the breast cancer setting and evaluation in clinical trial(s) as monotherapy or as combination therapy. ANGPT(L), angiopoietin(-like) protein; BRCA, breast cancer gene; ER, estrogen receptor; FGFR, fibroblast growth factor receptor; HER, human epidermal growth factor receptor; MET, hepatocyte growth factor receptor; PARP, poly (ADP-ribose) polymerase; PTEN, phosphatase and tensin homolog; RET, rearranged during transfection; TAM, tumor-associated macrophage.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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