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Page 2 of 17 Mooney et al. J Cancer Metastasis Treat 2019;5:19 I http://dx.doi.org/10.20517/2394-4722.2018.93

in BCC inhibition, leading to the development of a new targeted therapy for metastatic breast cancer.

Keywords: Metastasis, cancer cell, signaling, 3D culture, stem cells, EGFR, Wnt/β-catenin, NKD2

INTRODUCTION
Human breast cancer is currently the highest diagnosed form of cancer and the second leading cause of
cancer-related deaths in American women. Triple negative breast cancer is of the basal subtype and displays
poor prognosis owing to its highly metastatic properties. Current treatments focused on eradicating breast
tumors in lieu of or following local therapy include chemotherapy, hormonal therapy, and targeted therapy.
Hormonal therapy is not an option for triple negative breast cancer as it does not contain hormone receptors,
and there are currently no approved biological targeted therapies. Chemotherapy has proven unsuccessful
[1]
because triple negative breast cancer is highly drug resistant and is associated with high toxicity . It remains
a huge challenge to fully understand the mechanisms of cell migration and invasion of cancer cells, such
as triple negative breast cancer cells, and to eliminate these cancer cells to prevent disease recurrence and
metastasis.

Metastatic breast cancer cells have been linked to embryonic stem cells (ESCs) due to their sharing of
certain similar gene signatures and convergence of tumorigenic and embryonic pathways (e.g., EGFR,
Wnt/β-catenin, and TGF-β) [2-4] . ESC microenvironments have been exploited to restrict metastatic
potential of cancer cells [5-7] . In particular, our previous studies have shown that bioengineered 3D ESC
microenvironments using alginate hydrogels have great potential to supply critical signaling molecules
and reprogram highly aggressive breast cancer cells to a non-invasive phenotype [4,8-10] , including decreased
cell proliferation, increased apoptosis, reduced cell migration, invasion and metastatic marker expression,
reversed epithelial-mesenchymal transition (EMT), and altered cell metabolism of metastatic breast cancer
cells. The engineering of unique ESC microenvironments in vitro which can restrict the metastatic potential
of triple negative breast cancer cells (BCCs) may permit advanced study of cancer metastasis. Consequently,
this could provide greater insight into the decision-making processes regarding the growth, migration, and
invasion of cancer cells and its subsequent prevention.

The EGFR and canonical Wnt/β-catenin signaling pathways control many cell properties that contribute
to the metastatic phenotype. The EGFR (also known as the ErbB1/HER1) belongs to the ErbB family of
tyrosine kinase receptors. Binding of ligands (e.g., EGF, TGF-α) to the EGFR initiates dimerization of the
EGFR with one of the other three receptors within the same family. Dimerization activates the intracellular
tyrosine kinase domain, which undergoes autophosphorylation. This causes a conformational change which
exposes the activation loop and allows for protein binding and phosphorylation of downstream signaling
targets [11,12] . Phosphorylation initiates signaling cascades, such as Ras/Raf/mitogen-activated protein kinase/
ERK, phosphoinositol 3 (PI3)-Akt-mechanistic target of rapamycin (mTOR), PLC-γ, JAK/signal transducers
and activators of transcription (STAT), and Src kinase pathways [11-13] . These signaling pathways affect cell
growth and proliferation, differentiation, invasion, migration, apoptosis, angiogenesis, cell cycle progression,
and immune function [11,14,15] . The canonical Wnt/β-catenin signaling pathway is initiated when one of its
ligands binds to the receptor complex. This causes phosphorylation and activation of the protein dvl-1,
which inhibits a destruction complex normally responsible for recruitment, phosphorylation, ubiquitylation,
and proteasomal degradation of β-catenin. Signal activation and sequestration of the destruction complex
to the plasma membrane prevents the phosphorylation of β-catenin, which subsequently accumulates in
the cytoplasm, translocates to the nucleus, and activates transcription of target genes [16-19] . In human breast
[20]
cancer, β-catenin transactivates vimentin, a known EMT marker . β-catenin also forms a complex that
binds to the cytoplasmic tail of E-cadherin, connecting it to the actin cytoskeleton [21-24] .