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

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.

Figure 1. 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.

Figure 2. HIFs drive reprogramming of multiple metabolic pathways in breast cancer.

In general, HIF activity increases glycolysis and related carbohydrate pathways (e.g. pentose phosphate pathway and glycogen metabolism) as well as lactate export while suppressing mitochondrial O₂-dependent metabolism. Amino acid, acetate, and fatty acid uptake are increased to fuel processes that are essential for formation of ROS scavengers and Krebs cycle intermediates. This metabolic rewiring not only allows rapid proliferation and protects cells from ROS-induced damage but also contributes to formation of breast cancer stem cells and generation of an acidic and nutrient-depleted immunosuppressive microenvironment. Drugs with their respective targets or nonpharmaceutical, patient-centered strategies that target the rewired metabolism in breast cancer are listed in blue text. The key notes their furthest stage of (pre)clinical development in the breast cancer setting and/or evaluation in clinical trial(s) as monotherapy or as combination therapy. 1CM, one-carbon metabolism; 2-DG, 2-deoxyglucose; ACC, acetyl-CoA carboxylase; ACSS, acetyl-CoA synthetase; ALDO, aldolase; BNIP3, BCL2- and adenovirus E1B 19-kDa–interacting protein 3; CA, carbonic anhydrase; ETC, electron transport chain; FABP, fatty acid–binding protein; FAO, fatty acid oxidation; FASN, fatty acid synthase; G6PD, glucose-6-phosphate dehydrogenase; GAA, α-1,4-glucosidase; GBE, glycogen branching enzyme; GLUT, glucose transporter; GSH, glutathione; GYS, glycogen synthase; HK, hexokinase; α-KG, α-ketoglutarate; LDHA, lactate dehydrogenase A; MCT, monocarboxylate transporter; NBC, Na⁺-bicarbonate cotransporter; NHE, Na⁺/H⁺ exchanger; PDK, pyruvate dehydrogenase kinase; PFK, phosphofructokinase; PGK, phosphoglycerate kinase; PHGDH, phosphoglycerate dehydrogenase; PPP, pentose phosphate pathway; PYG, glycogen phosphorylase; SLC, solute carrier; SNAT, sodium-coupled neutral amino acid transporter.

Figure 3. Approaches to measure HIF activity, cancer angiogenesis, and metabolism.

Depending on the method and the scale of application, various degrees of detail, intratumor and intrapatient heterogeneity, and interpatient heterogeneity can be captured. ANGPTL, angiopoietin-like protein; BOLD, blood oxygenation level–dependent; CA, carbonic anhydrase; Cu-ATSM, copper(II)-diacetyl-bis(N⁴-methylthiosemicarbazone); DCE, dynamic contrast–enhanced; ¹⁸F-FAZA, ¹⁸F-fluoroazomycin arabinoside; ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; ¹⁸F-MISO, ¹⁸F-fluoromisonidazole; GEO, Gene Expression Omnibus; MRSI, magnetic resonance spectroscopic imaging; PET/CT, positron emission tomography/computed tomography; TCGA, The Cancer Genome Atlas; Tie2, TEK receptor tyrosine kinase 2.