Table 1 QNBC biomarkers and therapeutic targets, based upon differences in tumor biology between AR-negative and AR-positive TNBCs, and suggested therapeutic interventions
From: Quadruple-negative breast cancer: novel implications for a new disease
QNBC biomarkers and therapeutic targets | Genomic and molecular features (relative expression to AR+) | Prospective therapy |
|---|---|---|
Cell growth and proliferation | ||
EGFR (epidermal growth factor receptor) | Higher expression; indicates increased cellular growth and proliferation | Tyrosine kinase inhibitors (gefitinib and erlotinib) and anti-EGFR monoclonal antibodies (cetuximab) [63,64,65,66,67] |
HER4 (human epidermal growth factor receptor 4) | Lack of expression; may serve as a prognostic biomarker | Not a therapeutic target; only a prognostic biomarker [68,69,70] |
Ki-67 | Enhanced expression, i.e., high proliferation index | Anthracycline/taxane-based chemotherapy [12, 71,72,73,74,75,76] |
CK 5/6 (cytokeratin 5/6) | Enhanced expression | |
TOPO2A (topoisomerase IIα) | Elevated levels | Anthracycline, topoisomerase I/II inhibitors and PI3K/AKT/mTOR inhibitors [77, 78] |
PTEN (phosphatase and tensin) | Decreased expression | |
CDK6 (cyclin-dependent kinase 6) | Increased mRNA expression | |
Cell metabolism | ||
ASCL4 (acyl-CoA synthetase 4) | - Elevated expression associated with claudin-low and basal-like BC phenotypes; may boost arachidonic acid metabolism through PTGS2, ALOX5, and AKT/mTOR pathways | - Synergistic effect of ACSL4 inhibitor (e.g., rosiglitazone) and mTOR inhibitor (e.g., rapamycin) |
- May serve as a therapeutic biomarker | - Downregulation of ASCL4 upregulates ER and AR expression in vitro; ASCL4 inhibition may create sensitivity to hormone-targeted therapies such as tamoxifen and anti-AR agents [81,82,83,84,85] | |
Tumor immune microenvironment | ||
PD-L1 (programmed death-ligand 1) | Higher expression | Immune checkpoint inhibitors (i.e., pembrolizumab) [86] |
TIL (tumor-infiltrating lymphocytes) | Higher peripheral and stromal levels (suggests increased anti-tumor immune activity); positively correlates with EGFR, BRCA1, β-catenin expression in early-stage QNBC | EGFR-targeted therapies, platinum agents, and Wnt/β-catenin small molecule inhibitors [87,88,89] |
TNFSF10 (tumor necrosis factor superfamily member 10) | Lower mRNA expression (suggests decreased anti-tumor immune activity) | Potential susceptibility to cytokine-based immunotherapy to stimulate anti-tumoral immunity [68, 90] |
Organellular level | ||
CA20 gene set | Higher centrosome amplification (CA) and CA20 score | Centrosome declustering drugs (griseofulvin, noscapine), HSET inhibitors (CW069, AZ82), PARPi (PJ34, GF-15) [91,92,93,94,95,96,97,98,99] |