Triple-Negative Breast Cancer: Current Understanding and Future Therapeutic Breakthrough Targeting Cancer Stemness

Abstract

Triple-negative breast cancer (TNBC) is cancer that tested as negative for estrogen receptors (ER), progesterone receptors (PR), and excess human epidermal growth factor receptor 2 (HER2) protein which accounts for 15%-20% of all breast cancer cases. TNBC is considered to be a poorer prognosis than other types of breast cancer, mainly because it involves more aggressive phenotypes that are similar to stem cell-like cancer cells (cancer stem cell, CSC). Thus, targeted treatment of TNBC remains a major challenge in clinical practice. This review article surveys the latest evidence concerning the role of genomic alteration in current TNBC treatment responses, current clinical trials and potential targeting sites, CSC and drug resistance, and potential strategies targeting CSCs in TNBC. Furthermore, the role of insulin-like growth factor 1 receptor (IGF-1R) and nicotinic acetylcholine receptors (nAChR) in stemness expression, chemoresistance, and metastasis in TNBC and their relevance to potential treatments are also discussed and highlighted.

Keywords: Cancer stem cell; IGF-1R; Recurrence; Resistance; TNBC; nAChR.

Figure 1

Diagram of ongoing clinical trials in TNBCs. (A) System view of signaling pathways activated by extracellular stimuli, which triggered multiple biological functions through central hub AKT or subsequent effectors. Numerous inhibitors attempt to attack these critical molecules in TNBCs, and ongoing phases of clinical trials for categorized inhibitors have also revealed the same. (B) Disruption of cell cycle by CDK inhibitors in TNBC trials. (C) Blockade of immune checkpoints in cancer immunotherapy. Prevention of PD-1/PD-L1 signaling transduction from inhibitors could activate CD8⁺ T cells to kill TNBC tumor cells.

Figure 2

Diagram of ongoing clinical trials of potential targeting strategies against CSCs in carcinoma. System view of signaling pathways activated by extracellular stimuli, which triggered multiple biological functions through subsequent effectors. Numerous inhibitors and inducer attempt to attack either these critical molecules or pathways in CSCs in several types of carcinoma.

Figure 3

Diagram of molecular pathways involving in CSC drug resistance. System view of drug resistance, which triggered by multiple pathways through subsequent effectors. Some effectors can cross-talk to other molecules leading to stimulate different biological functions, which cooperatively play roles in drug resistance in CSCs. EMT: epithelial-mesenchymal transition; SDR: spontaneous drug resistance; CTC: circulating tumor cell; UPR: unfolded protein response; ERS: endoplasmic reticulum stress; DDR: DNA damage response; ROS: reactive oxygen species; CAF: cancer-associated fibroblast.