Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies

Abstract

Triple-negative breast cancer (TNBC) cells are deficient in estrogen, progesterone and ERBB2 receptor expression, presenting a particularly challenging therapeutic target due to their highly invasive nature and relatively low response to therapeutics. There is an absence of specific treatment strategies for this tumor subgroup, and hence TNBC is managed with conventional therapeutics, often leading to systemic relapse. In terms of histology and transcription profile these cancers have similarities to BRCA-1-linked breast cancers, and it is hypothesized that BRCA1 pathway is non-functional in this type of breast cancer. In this review article, we discuss the different receptors expressed by TNBC as well as the diversity of different signaling pathways targeted by TNBC therapeutics, for example, Notch, Hedgehog, Wnt/b-Catenin as well as TGF-beta signaling pathways. Additionally, many epidermal growth factor receptor (EGFR), poly (ADP-ribose) polymerase (PARP) and mammalian target of rapamycin (mTOR) inhibitors effectively inhibit the TNBCs, but they face challenges of either resistance to drugs or relapse. The resistance of TNBC to conventional therapeutic agents has helped in the advancement of advanced TNBC therapeutic approaches including hyperthermia, photodynamic therapy, as well as nanomedicine-based targeted therapeutics of drugs, miRNA, siRNA, and aptamers, which will also be discussed. Artificial intelligence is another tool that is presented to enhance the diagnosis of TNBC.

Keywords: artificial intelligence; immunotherapy; nanomedicine; theranostics; triple negative breast cancer.

Figure 1

Diagram of Notch receptor activation and therapeutic target in clinical development. Notch signaling is initiated by ligand binding to Notch receptor, which undergoes a two-step proteolytic cleavage by ADAM family proteases and γ-secretase, releasing the Notch intracellular domain (NICD). The NICD translocates to the nucleus where it binds to CSL and converts the complex from a repressor to an activator of Notch target genes. Notch signaling could be inhibited by two major classes of Notch inhibitors: γ-secretase inhibitors and monoclonal antibodies directing against Notch receptors or ligands. Abbreviations: NEC, Notch extracellular subunit; NTM, Notch transmembrane fragment; NEXT, Notch extracellular truncated; CSL, C protein binding factor 1/Suppressor of Hairless/Lag-1; NICD, Notch Intracellular Domain. Reproduced with permission from Yuan X, Wu H, Xu H, Xiong H, Chu Q, Yu S. Notch signaling: An emerging therapeutic target for cancer treatment. Cancer Letters. 2015, 369, 20–27 [34].

Figure 2

Canonical Wnt Pathway and Inhibitors of the Wnt/beta-Catenin Signaling Pathway schematic representation of the Canonical Wnt Pathway and pharmacologic inhibitors of the Wnt/beta-catenin signaling pathway. Reproduced with permission from Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin Pathway in Cancer: Update on Effectors and Inhibitors. Cancer Treatment Reviews. 2018, 62, 50–60 [56].

Figure 3

Poly (ADP-ribose) polymerase (PARP) inhibitor treatment of BRCA-1/2-associated and sporadic cancers. Reproduced with permission from Leif W. Ellisen. PARP Inhibitors in Cancer Therapy: Promise, Progress, and Puzzles. Cancer Cell. 2011, 19(2), 165–167 [66].

Figure 4

Mammalian target of rapamycin (mTOR) signaling pathway. mTOR is a subunit of two distinct multi-protein complexes, mTORC1 and mTORC2. Both mTORC1 and mTORC2 can be activated in response to growth-factors stimulation, whereas mTORC2 is a major kinase that phosphorylates and activates Akt. The importance of mTORC1 and mTORC2 in regulation of multiple cell functions vital for development of cancer and their strong interaction with oncogenic pathways make mTOR an attractive target for therapeutic intervention. The mechanisms of action of currently available mTOR inhibitors are shown. Reproduced with permission from Zaytseva YY, Valentino JD, Gulhati P, Evers BM. mTOR inhibitors in cancer therapy. Cancer Letters. 2012, 319, 1–7 [68].

Figure 5

A schematic representation of the activators, inhibitors and outcomes of epidermal growth factor receptor (EGFR) signaling. EGFR is part of the four-member ErbB superfamily (ErbB1–4). These receptors form several different homo- and heterodimers (here we only depict the EGFR homodimer). EGFR is capable of binding several different extracellular ligands that agonize the receptor leading to activation of several downstream signaling events including, but no limited to those listed. Several therapeutics have been developed to antagonize EGFR including monoclonal antibodies (mAbs) that block ligand binding as well as several different kinase inhibitors. In addition to EGFR, some of these kinase inhibitors also target other ErbB receptors, supporting their use in human epidermal growth factor receptor-2 (Her2)-amplified breast cancer (BC). All of the listed therapies are Food and Drug Administration (FDA) approved for various cancers with the exception of Neratinib. Reproduced with permission from Ali R and Wendt MK. The paradoxical functions of EGFR during breast cancer progression. Signal Transduction and Targeted Therapy 2017, 2(16042), 1–7 [81].

Figure 6

Therapeutic targeting of the hallmarks of cancer drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use in treating certain forms of human cancer. Additionally, the investigational drugs are being developed to target each of the enabling characteristics and emerging hallmarks depicted in Figure 3, which also hold promise as cancer therapeutics. The drugs listed are but illustrative examples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in development for most of these hallmarks. Reproduced with permission from Hanahan & Weinberg. Hallmarks of Cancer: The Next Generation, Cell 144, 4 March 2011 Elsevier Inc. 2011,144(5), 646–674 (215).