Triple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs

Abstract

Metastatic progression and tumor recurrence pertaining to TNBC are certainly the leading cause of breast cancer-related mortality; however, the mechanisms underlying TNBC chemoresistance, metastasis, and tumor relapse remain somewhat ambiguous. TNBCs show 77% of the overall 4-year survival rate compared to other breast cancer subtypes (82.7 to 92.5%). TNBC is the most aggressive subtype of breast cancer, with chemotherapy being the major approved treatment strategy. Activation of ABC transporters and DNA damage response genes alongside an enrichment of cancer stem cells and metabolic reprogramming upon chemotherapy contribute to the selection of chemoresistant cells, majorly responsible for the failure of anti-chemotherapeutic regime. These selected chemoresistant cells further lead to distant metastasis and tumor relapse. The present review discusses the approved standard of care and targetable molecular mechanisms in chemoresistance and provides a comprehensive update regarding the recent advances in TNBC management.

Keywords: ABC transporters; DNA damage; chemoresistance; metabolic reprogramming; novel therapies; signaling; triple-negative breast cancer.

Figure 1

Therapeutic approaches to target specific pathways in TNBC. Inhibitors are mentioned in italics. (AR = androgen receptor; T = testosterone; DHT = dihydrotestosterone; PARP = poly (ADP-ribose) polymerase; XRCC1 = X-ray repair cross-complementing protein 1; Pol = polymerase); VEGF = vascular endothelial growth factor; VEGFR = VEGF receptor; EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; TK = tyrosine kinase; PI3K = phosphoinositide 3-kinase; AKT = protein kinase B; mTOR = mammalian target of rapamycin; APC = antigen-presenting cell; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; CD80 = cluster of differentiation 80; CD86 = cluster of differentiation 86; PD-1 = programmed cell death protein 1; PD-L1 = programmed death-ligand 1).