A review of biological targets and therapeutic approaches in the management of triple-negative breast cancer

Abstract

Background: Triple-negative breast cancer (TNBC) is a heterogeneous, aggressive phenotype of breast cancer with associated chemoresistance. The development of chemo- or radioresistance could be attributed to diverse tumor microenvironments, overexpression of membrane proteins (transporters), epigenetic changes, and alteration of the cell signaling pathways/genes associated with the development of cancer stem cells (CSCs).

Aim of review: Due to the diverse and heterogeneous nature of TNBC, therapeutic response to the existing modalities offers limited scope and thus results in reccurance after therapy. To establish landmark therapeutic efficacy, a number of novel therapeutic modalities have been proposed. In addition, reversal of the resistance that developed during treatment may be altered by employing appropriate therapeutic modalities. This review aims to discuss the plethora of investigations carried out, which will help readers understand and make an appropriate choice of therapy directed toward complete elimination of TNBC.

Key scientific concepts of review: This manuscript addresses the major contributory factors from the tumor microenvironment that are responsible for the development of chemoresistance and poor prognosis. The associated cellular events and molecular mechanism-based therapeutic interventions have been explained in detail. Inhibition of ABC transporters, cell signaling pathways associated with CSCs, and epigenetic modification offers promising results in this regard. TNBC progression, invasion, metastasis and recurrence can also be inhibited by blocking multiple cell signaling pathways, targeting specific receptors/epigenetic targets, disrupting bioenergetics and generating reactive oxygen species (ROS).

Keywords: Cancer stem cells; Chemoresistance; Epigenetics; Therapeutic modality; Triple-negative breast cancer (TNBC); Tumor microenvironment.

Graphical abstract

Fig. 1

Schematic representation of the development of resistance in advanced TNBC after radiation and chemotherapy. The early stage of the TNBC are highly sensible to the chemotherapy and could control the tumor growth in mammary region. The tumor elimination can be done chemotherapy followed by the surgery and radiation therapy. However, the advanced TNBC, is associated with the TME and related phenotypes, thus the TNBC cells acquired resistance to the chemo-/radiation therapies.

Fig. 2

Tumor cell interactions with the tumor microenvironment. The heterogeneous microenvironments of tumors are associated with the formation of new blood vessels (angiogenesis), immune suppression, metabolic alteration (low nutrient adaptation), conversion of cells (cell differentiation), induced hypoxic conditions and developed resistance to therapies. Cancer-associated fibroblasts (CAFs), Stromal cell-derived factor 1 (SDF-1), Transforming growth factor beta (TGF-beta), Tumor-infiltrating lymphocytes (TILs), Tumor-associated macrophages (TAMs), Vascular endothelial growth factor (VEGF).

Fig. 3

The microenvironment of cancer stem cells. Proliferation, self-renewal, differentiation, metastasis, and tumorigenesis of CSCs in the CSC microenvironment. Chemokines-7 (CXCL-7), Chemokines-7 (CXCL-7), Hepatocyte Growth Factor (HGF), Hypoxia-inducible factor-α (HIF- α), Interleukin-β (IL-β), Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Stromal cell-derived factor 1 (SDF-1), Vascular endothelial growth factor (VEGF). Wnt, Notch, JAK/STAT3, NF-κB, Notch, Hedgehog, and AKT/mTOR are cell signaling pathways.

Fig. 4

Graphical representation of the mechanism of PARP inhibitors in the treatment of TNBC associated with the BRCA gene. Adapted from .

Fig. 5

Mechanistic representation of bevacizumab, a VEGF inhibitor, in the inhibition of angiogenesis in TNBC.

Fig. 6

Receptor-mediated drug delivery for the treatment of TNBC.