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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.

Original publication

DOI

10.1172/JCI137552

Type

Journal article

Journal

J Clin Invest

Publication Date

01/10/2020

Volume

130

Pages

5074 - 5087

Keywords

Animals, Basic Helix-Loop-Helix Transcription Factors, Biomarkers, Tumor, Breast Neoplasms, Female, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Models, Biological, Neovascularization, Pathologic, Prognosis, Signal Transduction, Tumor Microenvironment