The Role of Hypoxia-Inducible Factor Isoforms in Breast Cancer and Perspectives on Their Inhibition in Therapy
Abstract
:Simple Summary
Abstract
1. Hypoxia in Normal and Cancer Cells
2. Hypoxia-Inducible Factors: Characteristics and Functions
3. Activation of the Hypoxia-Inducible Factor in Cancers
4. Effects of the HIF Activation
4.1. Metabolism
4.2. Evasion of the Immune Response
4.3. Cell Survival and Death
4.4. Angiogenesis, Invasion, and Metastasis
4.5. Cancer Stem Cells
4.6. HIFs Activity and Hormone Receptors
5. Perspectives on HIF’s Inhibition in Breast Cancer—To Inhibit or Not to Inhibit?
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Target Gene | HIF Isoform Regulation | Protein/RNA Role | References |
---|---|---|---|
A2BAR | HIF-1α | adenosine receptor 2A signaling in breast cancer cells promotes filopodia formation, invasion, and metastasis | [59] |
ADAM12 | HIF-1α and HIF-2α | disintegrin and metalloproteinase 12 (ADAM12); trim off the extracellular domain of the membrane-bound heparin-binding epidermal growth factor-like growth factor (HB-EGF), which binds to EGFR and triggers a signal transduction pathway involved in metastasis | [60] |
AMF | HIF-1α | autocrine motility factor; stimulates motility of cells under hypoxia | [61] |
ANGPTL4 | HIF-1α | angiopoietin-like 4; a secreted factor that inhibits EC-EC interaction | [62] |
BRK | HIF-1α and HIF-2α | Breast tumor kinase, increases migration via modulation of EMT -associated molecules | [63] |
CALR | HIF-1α | Calreticulin; facilitates invasion and metastasis by promoting the breast cancer stem cell phenotype through Wnt/β-catenin signaling | [64] |
CASP14 | HIF-1α | Caspase 14; breast cancer stem cell marker; has also been implicated as a gene found in brain-metastatic compared to non-brain metastatic breast cancer | [65] |
CKB | HIF-1α | Creatine kinase brain isoform, is a major effector of the HIF-1α-mediated promotion of metastatic phenotypes in ER-negative breast cancer | [66] |
CXCR3 | HIF-1α | CXCR3 is a Gαi G-protein coupled receptor (GPCR), a seven transmembrane spanning receptor; is the receptor for CXCL10 chemokine, increases migration | [67] |
CXCR4 | HIF-1α | CXCR-4 is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12); tumor cells overexpressing CXCR4, have higher potential to survive the circulation stage | [68,69] |
HCG18 | HIF-1α | Long Noncoding RNA HLA complex group 18; positively regulates the expression of BC-related ubiquitin-conjugating enzyme E2O (UBE2O) by sponging miR-103a-3p, thus promoting the malignant phenotypes of BC cells through the UBE2O/AMPKα2/mTORC1 axis. | [70] |
ITGA5 | HIF-1α and HIF-2α | integrin that binds to fibronectin, promotes lung metastasis in orthotopic transplantation models of triple negative breast cancer | [71] |
L1CAM | HIF-1α | L1 cell adhesion molecule; integral membrane glycoprotein belonging to a large class of immunoglobulin superfamily cell adhesion molecules (CAMs) that mediate cell-to-cell adhesion at the cell surface | [62] |
LncRNA BCRT1 | HIF-1α | Long Noncoding RNA (breast cancer-related transcript 1; promotes cell mobility and tumor metastasis in breast cancer; regulate the EMT process | [72] |
LncRNA EFNA3 | HIF-1α | Long Noncoding RNA ephrin A3, increases protein ephrin 3 levels by sequestering miRNAs away from EFNA3 mRNA allowing for its translation; | [73] |
LncRNA RAB11B-AS1 | HIF-2α | Long Noncoding RNA RAB11B-AS1; increases the expression of angiogenic factors including VEGFA and ANGPTL4 in hypoxic breast cancer cells through the recruitment of RNA Pol II | [74] |
LOX | HIF-1α | Lysyl Oxidase, post-translationally modifies collagen molecules in the extracellular matrix (ECM), regulates cell adhesion, motility and invasion; increases metastasis by enhancing premetastatic niche formation | [75,76,77] |
LOXL2 | HIF-1α and HIF-2α | lysyl oxidase-like 2; post-translationally modifies collagen which is a component of the extracellular matrix (ECM); promotes lung metastasis by facilitating the formation of the pre-metastatic niche | [32,77] |
MAFF | HIF-1α | v-maf musculoaponeurotic fibrosarcoma oncogene homolog F; transcription factor regulating tumor invasion and metastasis via IL11/STAT3 pathways activation; | [78] |
MMP1 | HIF-2α | degradation of the extracellular matrix MMP-1, mostly type I collagen, promotes tumor growth and metastasis particularly to the brain | [79] |
MMP2 | HIF-1α and HIF-2α | matrix metalloproteinase 2; degradation of extracellular matrix; degrades type IV collagen | [80,81,82] |
MMP9 | HIF-1α and HIF-2α | matrix metallopeptidase 9; degradation of the extracellular matrix | [32,83] |
MMP14/MT1-MMP | HIF-1α and HIF-2α | matrix metalloproteinase-14 or MT1-MMP, is a member of the membrane-type MMP subfamily; degradation of the extracellular matrix | [79] |
P4HA1 | HIF-1α and HIF-2α | prolyl 4-hydroxylase-α1; essential for collagen biogenesis; 4-hydroxyproline residues are necessary for the proper folding of collagen polypeptide chains into stable triple helical molecule; HIF-1α-dependent ECM remodeling increases cell motility and promote invasion and metastasis. | [79] |
P4HA2 | HIF-1α | prolyl 4-hydroxylase-α2; essential for collagen biogenesis; 4-hydroxyproline residues are necessary for the proper folding of collagen polypeptide chains into a stable triple helical molecule; HIF-1α-dependent ECM remodeling increases cell motility and promotes invasion and metastasis. | [79] |
PDGFB | HIF-1α | platelet-derived growth factor B; promotes, metastasis of hypoxic breast cancer cells via lymphatic dissemination | [84] |
PGF | HIF-1α | placental growth factor, promotes the metastasis of breast cancer cells; promotes recruitment of mesenchymal stem cell, to the primary tumor site and, stimulates them to the expression of CXCL10 | [67] |
SNAIL1 | HIF-2α | transcriptional factor; plays a key role in the control of epithelial to mesenchymal transition | [32] |
SLUG | HIF-1α | transcriptional factor; plays a key role in the control of epithelial to mesenchymal transition | [85], |
TWIST | HIF-1α | transcriptional factor; plays a key role in the control of epithelial to mesenchymal transition | [86] |
VEGF | HIF-1α | vascular endothelial growth factor; stimulates the formation of blood vessels | [87,88] |
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Kozal, K.; Krześlak, A. The Role of Hypoxia-Inducible Factor Isoforms in Breast Cancer and Perspectives on Their Inhibition in Therapy. Cancers 2022, 14, 4518. https://doi.org/10.3390/cancers14184518
Kozal K, Krześlak A. The Role of Hypoxia-Inducible Factor Isoforms in Breast Cancer and Perspectives on Their Inhibition in Therapy. Cancers. 2022; 14(18):4518. https://doi.org/10.3390/cancers14184518
Chicago/Turabian StyleKozal, Karolina, and Anna Krześlak. 2022. "The Role of Hypoxia-Inducible Factor Isoforms in Breast Cancer and Perspectives on Their Inhibition in Therapy" Cancers 14, no. 18: 4518. https://doi.org/10.3390/cancers14184518