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Page 10 of 20 Smigiel et al. J Cancer Metastasis Treat 2019;5:47 I http://dx.doi.org/10.20517/2394-4722.2019.26

increases aldehyde dehydrogenase 1 (ALDH1) activity [234,235] . IGF-1R activation signaling through PI3K/Akt/
mTOR represents a promising target in BC as an abnormal activation of PI3K can also lead to an increased
activation of STAT3 through enhanced expression of the chemokine (C-X-C motif) receptor 4 (CXCR4) [236,237] .
IGF-1R is activated in the 50% of breast cancer patients. Several phase III clinical trials targeting IGF-1R with
small molecule inhibitors have so far failed due to side effects such as hyperglycemia and metabolic syndrome
caused by the homology of IGF-1R and insulin receptor (IR) and IGF elevation in response to disruption of
glucose homeostasis. On the other hand, monoclonal antibodies specifically targeting IGF-1R or its ligand
have shown a higher specificity by sparing the insulin metabolism from any inhibitory effect in preclinical
models . Early phase trials have been setup to determine the efficacy of an antibody-based inhibition of
[238]
IGF-1R signaling by targeting either the receptor or the ligand in combination with aromatase inhibitors or
mTOR inhibitors but with small success . A more complex therapeutic protocol combining inhibitors of
[239]
PI3K or other downstream effectors of IGF-1R would probably be more beneficial.
Several drugs targeting the PI3K/mTOR pathway have shown a selective effect on CSCs, inhibiting their growth
and sensitizing them to traditional chemotherapy. Since 2007, when the Food and Drug Administration (FDA)
approved the mTOR inhibitor temsirolimus for the treatment of advanced renal carcinoma, new generations
of compounds have been developed. Everolimus, is a dual PI3K/mTOR inhibitor, which blocks all PI3K
class I isoforms as well as mTORC1 and 2, thus preventing the development of CSCs when combined with
letrozole [240,241] . Interestingly, mTOR is also inhibited by metformin (1,1-dimethylbiguanide hydrochloride),
usually prescribed for the treatment of type 2 diabetes. Metformin preferentially kills CSCs over non-CSCs
and reduces tumorsphere formation and CSC marker expression (CD133, CD44 and ALDH1) . Similar
[242]
effects have been achieved with the antibiotic salinomycin, which selectively kills breast CSC . The plant-
[243]
derived chemotherapeutic molecule rottlerin induces apoptosis in breast CSC by inhibiting PI3K/Akt/mTOR
pathway . More recently, the PI3K/mTOR dual inhibitor VS5584 has shown promising results by delaying
[244]
tumor recurrence through selective killing of CSC after chemotherapy .
[245]

Notch
Notch signaling is known to be involved in different cellular processes, including differentiation and
proliferation. Perturbation in these processes can be caused by mutations in Notch or one of its effectors.
Mutations of the Notch pathway are the hallmark of many subtypes of cancer, including BC, where cells
overexpressing Notch have increased CSC markers (SOX2 and OCT4) and phenotypes (tumorsphere
formation) [246-248] . Moreover, Notch promotes EMT and metastasis in TNBC cells and Notch inhibition can
prevent EMT both in vitro and in vivo . For example, 3,6-dihydroxiflavone (3,6-DHF) causes a significant
[249]
reduction of CSCs in vitro and blocks lung metastasis by specifically down regulating Notch, Hes-1 and
c-Myc . 3,6 DHF shows potent chemo-preventive properties against breast carcinogenesis both in vitro and
[250]
in vivo, although a mechanism has not been identified yet, besides an epigenetic increase in the synthesis
of miR-34a, a potent down-regulator of Notch and thus of EMT in breast cancer . Furthermore, 3,6-
[251]
DHF down-regulates the expression of Notch’s target genes Hes1, c-Myc and the EMT mediators SNAIL,
Twist and Slug by compromising the formation of the transcriptional complex NICD-CSL-MAML [252,253] .
More recently, it has been shown that Notch3 inhibition by siRNA silencing increases TNBC sensitivity to
gefitinib in EGFR-Tyrosine kinase inhibitors (TKI)-resistant cells by blocking the nuclear translocation of
activated EGFR .
[254]
Wnt and β-catenin
The Wnt pathway is involved in the maintenance of breast CSCs by promoting self-renewal and plasticity
through PAF (proliferating cell nuclear antigen-associated factor) . The Wnt ligand, Frizzled, is upregulated
[255]
in high-grade tumors, including more aggressive forms of BC, and can cause EMT and metastasis through
non-canonical STAT3 activation . Inhibitors targeting the Wnt pathway have been developed and are
[256]
showing promise in BC models. In particular, the Wnt/beta-catenin inhibitor CWP232228, which blocks