Breast Cancer Stem Cells and Tumor Heterogeneity: Characteristics and Therapeutic Strategies

Abstract

Breast cancer is one of the most frequently detected malignancies worldwide. It is responsible for more than 15% of all death cases caused by cancer in women. Breast cancer is a heterogeneous disease representing various histological types, molecular characteristics, and clinical profiles. However, all breast cancers are organized in a hierarchy of heterogeneous cell populations, with a small proportion of cancer stem cells (breast cancer stem cells (BCSCs)) playing a putative role in cancer progression, and they are responsible for therapeutic failure. In different molecular subtypes of breast cancer, they present different characteristics, with specific marker profiles, prognoses, and treatments. Recent efforts have focused on tackling the Wnt, Notch, Hedgehog, PI3K/Akt/mTOR, and HER2 signaling pathways. Developing diagnostics and therapeutic strategies enables more efficient elimination of the tumor mass together with the stem cell population. Thus, the knowledge about appropriate therapeutic methods targeting both "normal" breast cancer cells and breast cancer stem cell subpopulations is crucial for success in cancer elimination.

Keywords: BCSC; biomarkers; breast cancer subtypes; signaling pathways; therapy.

Figure 1

Pathways associated with the signaling of BCSCs. Canonical activation of Hedgehog (Hh) signaling is initiated by the binding of the Hh ligand to PTCH1, which exits the primary cilium (PC), relieving SMO’s inhibition and resulting in SMO’s translocation into the PC. In the lack of HH ligands, PTCH1 inhibits SMO by disturbing its entry into the PC. GLI2 and GLI3 are sequestered in the cytoplasm by SUFU and phosphorylated by PKA, CK1, and GSK3β. GLI1 is fully degraded, while GLI3 and GLI2 undergo fragmentary proteasome degradation. This leads to the creation of GLI3/2R, which moves into the nucleus, resulting in the inhibition of the GLI target gene transcription. GLI2 and GLI3 processing is disturbed by active SMO, which initiates their dissociation from SUFU, and translocation of full-length, active GLI (GLIACT) into the nucleus, resulting in the activation of GLI target gene transcription. Cadherins modulate Wnt/β-catenin signaling. The level of free β-catenin in the cytoplasm directly affects the degree of β-catenin accumulation in the nucleus. Free β-catenin has a short half-life due to its phosphorylation by GSK3 and destruction upon binding to the adenomatous polyposis coli (APC) and Axin proteins. GSK3 activity is reduced by disheveled (DSH) when the Wnt growth factor binds to its surface receptor Frizzled (FZD). Notch signaling DSL (Delta/Serrate/Lag-1) ligands binding changes the conformation of the Notch receptor. The ADAM family arbitrates the first cleavage, which leads to the separation of the extracellular domain. A second cleavage then occurs inside the transmembrane domain and is catalyzed by the γ-secretase complex, which releases NICD for translocation to the nucleus. In the nucleus, NICD binds to the DNA-binding protein RBP-J, leading to Notch target genes’ transcription. CSL is a DNA-binding protein that recruits NICD to Notch target gene promoters. Schematic presentation of the PI3K/Akt/mTOR signaling pathway: Ligands bind to the receptor tyrosine kinases like Her2, which leads to conformational changes and activates PI3K. PI3K initiates activation of Akt by phosphorylation, which acts as a major activation source to further downstream signaling moieties involved in various cellular processes (mTOR).