Stem cell therapy: A paradigm shift in breast cancer treatment

Table 1 Pathways and factors influencing cancer stem cells

Factors/pathways	Role in cancer stem cells	Ref.
MicroRNAs	Involved in modulation of genes associated with CSC pathways such as Notch, Wnt/β-catenin, hedgehog, PI3K, NF-κB, etc. miR-9, miR-22, miR-155, mi-181, miR-221/222 and miR-373 are upregulated in CSCs and promote tumor invasiveness and stemness	Akbarzadeh et al[28] and Lapidot et al[29]
Notch	Aberrant expression in CSCs with upregulation of stemness genes such as ALDH, Sox2, Oct4, klf4 lead to increased self-renewal stem cell property. Notch 1 upregulates transcription of RTK ErbB2 gene, influencing self-renewal property of CSCs. Notch 4 induces the expression of Snail homolog 2, an EMT mediator hence imparting quiescent mesenchymal phenotype in BCSCs	Pannuti et al[39], Suman et al[40] and Harrison et al[41]
Hedgehog	Hh signaling regulates self-renewal property of stem cells by activating polycomb gene BMI-1. GLI1/GLI2 transcription factors or Hh ligand overexpression cause mammosphere formation and cancer stem cell growth. Hh signaling leads to upregulation of stemness markers c-myc, Nanog, Oct 4. BCSCs markers CD44 and ALDH1. Invasion and EMT promoting Snail and Wnt and jagged ligands	Liu et al[48]
Wnt	Elevated Wnt signaling in BCSCs increases tumorigenicity and metastases, and conversely abrogation of Wnt decreases tumorigenicity. CSCs shows upregulated expression of various Wnt downstream molecules; LEF1, β-catenin and TCF-4. β-catenin complexes with the TCF/LEF and leads to the transcription of several target genes involved in CSC initiation, maintenance, invasion and metastasis such as lgr5, c-Myc, c-Jun, cyclin D1, MMP7 and fibronectin	Monteiro et al[109], Jang et al[110], and Kalluri and Weinberg [111]
PI3K	Differentially expressed in the cancer stem cell subpopulation leading to enhanced survival. Strong correlation between PI3K pathway and programmed cell death-ligand 1 could account for stemness in claudin low breast cancer subtypes, as it causes the upregulation of Oct-4A, Nanog and Bmi1 genes. Bmi1 plays a significant role in the self-renewal of BCSCs (CD44+/CD24–/Lin–) as it transcriptionally downregulates PTEN, thereby leading to enhanced PI3K signaling	Liu et al[48] and Magee et al[75]
HER2	HER2 containing heterodimers can activate key signaling proliferative pathways like RAS/Raf/MAPK pathway and the cell survival PI3K/Akt pathway. HER2 overexpression generates multidrug resistance phenotype acting via the PI3K/ Akt pathway	Karunagaran et al[112] and Ren and Schaefer[113]
NF-κB	One important target of transcription factor NF-κB is CD44 whose expression is increased in cancer stem cells. NF-kB regulates the ECM modifying matrix MMP9. Inhibition of NF-κB could result in repression of CD44 and MMP9 and lead to decreased invasiveness in breast cancer cells	So et al[114], Yu and Stamenkovic[115], and Smith et al[116]
BRCA1	Loss of BRCA1 responsible for aggressive basal-like breast cancer and expansion of BCSCs. Silencing of BRCA1 expression by siRNA transitions cells to acquire stemness features	Miki et al[24], Lim et al[25] and Heerma van Voss et al[117]
Hypoxia	Upregulates genes associated with CSCs thereby allowing long-term self-renewal capacity and a blocking of differentiation. Inhibits BRCA1 expression and downregulation of BRCA1 protein. Upregulates BCSC pool	Ungefroren et al[118], Lin and Yun[119], and Xie et al[120]

CSC: Cancer stem cell; BCSCs: Breast cancer stem cells; NF-κB: Nuclear factor kappa beta; PI3K: Phosphatidylinositol 3-kinase; Hh: Hedgehog; EMT: Epithelial mesenchymal transitions; miR: MicroRNA; ALDH: Aldehyde dehydrogenase; LEF: Lymphoid enhancer-binding factor; HER2: Epidermal growth factor receptor 2; ECM: Extracellular matrix; BRCA1: Breast cancer type 1; siRNA: Silencing RNA.

Table 2 Clinical trials targeting stemness pathways

Drug	Action	Clinical trial phase	NCT number
Glasdegib	Notch pathway inhibitor	Phase I	NCT02027376
LGK-974	Inhibitor of the endogenous Wnt palmitoleoylase	Phase I	NCT01351103
Sonidegib	Smo inhibitor of the Hedgehog signaling pathway	Phase I/II	NCT02027376
Gedatolisib	Targets the PI3K/mTOR pathway in TNBC or advanced breast cancers	Phase I/II	NCT03911973
Bevacizumab	Targets VEGF signaling	Phase I/II	NCT01190345
Ribociclib	CDK4/6 inhibitors in metastatic breast cancer	Phase II	NCT02738866
Anti-PTK7 antibody-drug conjugate	Targets PTK7 in BCSCs	Phase I/II	NCT03243331
MEDI4736	Antibody against PD-L1	Phase II	NCT02685059
Abemaciclib	CDK4/6 inhibitors in metastatic breast cancer	Phase II	NCT03703466
Bivatuzumab	Targeting stem cell surface marker CD44v6	Phase 1	NCT02254005

VEGF: Vascular endothelial growth factor; PTK7: Protein tyrosine kinase 7; PI3K: Phosphatidylinositol 3-kinase; TNBC: Triple-negative breast cancer; PD-L1: Programmed cell death-ligand 1; BCSCs: Breast cancer stem cells; CDK: Cyclin dependent kinase.