Table 1.
Molecular mechanisms and potential therapeutic targets in breast cancer brain metastasis
| Mechanism | Potential Therapeutic Target | Location | Regulated by | Regulates | Action | Reference |
|---|---|---|---|---|---|---|
| Passage through BBB | Wnt5A/ROR1; Wnt5B/ ROR2 | NA | Wnt signaling | NA | ↑ invasion | 15 |
| αvβɜ integrin | NA | NA | ↑ tumor-platelet interaction | ↑ arrest in vasculature | 29 | |
| αvβɜ integrin | NA | NA | ↑ VEGF | ↑ intracerebral growth | 30 | |
| β4 integrin signaling | NA | NA | ↑ VEGF | ↑ disruption of inter- endothelial junctions | 31 | |
| β1 integrin | NA | NA | NA | ↑ adhesion | 32 | |
| P-selectin | endothelial cells and activated platelets | NA | communication/ protection of arrested TC | ↑ metastatic ability | 34 | |
| CXCL12/CXCR4 signaling | metastatic site/ TC | NA | ↑ PI3K/Akt | ↑ adhesion, ↑ TEM | 36 | |
| NF-κB signaling | NA | CXCR4 | organ-specific metastasis of breast cancer | ↑ migration, ↑ tumor growth | 38 | |
| Intracerebral progression | CD44+/ CD24− phenotype | breast cancer cells | NA | ↑ IL-1α, ↑ IL-6, ↑ IL-8, ↑ uPA | ↑ invasion | 25 |
| uPA | breast cancer cells | NF-κB pathway | Plasmin production, MMPs | ↑ ECM cleavage | 28 | |
| ↓ Plasmin | NA | ↑ neuroserpin, ↑ serpin B2, ↑ L1CAM | NA | ↑ TEM | 27 | |
| Interaction with astrocytes | IL-1β, TNF-α, TGF-β, IL-6 | Astrocytes | NA | NA | ↑ proliferation (breast and lung cancer cells) | 41 |
| cyclic GAMP | Astrocytes | TCs | ↑ INFα, ↑ TNF ->↑STAT1 and NF-κB pathways | ↑ tumor growth, ↑ chemo-resistance | 42 | |
| Akt/MAPK pathways | TCs | astrocytes-TC interaction | ↑ GSTA5, ↑ BCL2L1, ↑ TWIST1 | ↑ resistance, ↑ survival | 43 | |
| IL-1β | (secreted by) BM breast cancer | NA | ↑ JAG1 | ↑ Notch signaling | 44 | |
| Interaction with ECM | MMP-14 (or MT1-MMP) | target site | COX-2 (or PTGS2) | MMP-2 | ↑ TEM | 47 |
| MMP1 | (secreted by) breast cancer cells | NA | degrades tight junctions of BBB | ↑ TEM | 48 | |
| HPSE | BM breast cancer, endothelial cells and glial cells | EGFR/Her2 signaling | NA | ↑ TEM | 53 | |
| HPR1 | NA | ↓ HS | NA | ↑ metastatic ability | 55 | |
| CTSB | breast cancer cells | NA | ↑ angiogenesis, ↑ MMPs | ↑ ECM cleavage, ↑ invasion, ↑ tumor growth | 57 | |
| CTSS | NA | NA | proteolytic processing of JAM-B | ↑ TEM | 59 | |
| Cav-1 | NA | NA | ↓ MMP-9 and MMP-2, ↓ STAT3 / (LSS exposure):↑ PI3K/Akt/mTOR signaling | ↓ tumor growth, ↓ invasion / (LSS exposure):↑ motility, ↑ invadopodia formation, ↑ invasion | 60,61 | |
| MEK5 | NA | STAT3 | ↑ EMT | ↑ invasion | 64 | |
| exo-AnxA2 | breast cancer cells | NA | ↑ p38MAPK, ↑NF-κB, ↑ stat3 pathways; (secretion of):↑ IL-6, ↑ TNF-α | ↑ angiogenesis, ↑ proliferation | 65 | |
| TUBB3 | breast cancer BM cell line | NA | NA | ↑ metastatic ability | 66 | |
| AngII | vasoactive peptide | NA | ↑ MMP-2, ↑ MMP-9 in breast cancer cells; ↑ICAM-1 | ↑ adhesion, ↑ TEM, ↑ motility | 67 | |
| CRYAB | (independent predictor of BM) | NA | NA | ↑ adhesion, ↑ TEM | 68,69 | |
| Ang-2 | activated brain endothelial cells | VEGF secreted by TN breast cancer cells | impairment of TJ structures | ↑ TEM | 70 |
Akt, protein kinase B; TEM, transendothelial migration; L1CAM, L1 cell adhesion molecule; TNF, tumor necrosis factor; TGF, tumor growth factor; cGAMP, cyclic guanosine monophosphate–adenosine monophosphate; INF, interferon; GSTA5, glutathione S-transferase alpha 5; BCL2L1, BCL2 like 1; TWIST1, twist family BHLH transcription factor 1; JAG1, jagged 1; PTGS2, prostaglandin-endoperoxide synthase 2; JAM-B, junctional adhesion molecule B; Cav-1, caveolin-1; LSS, low shear stress; MEK5, mitogen extracellular-signal-regulated kinase 5; exo-AnxA2, exosomal-annexin A2; ICAM-1, intercellular adhesion molecule 1; CRYAB, αβ-crystallin; TN, triple negative; TJ, tight junction; NA, not available