Page 116 - Read Online

Page 300 Ponnusamy et al. Cancer Drug Resist 2019;2:297-312 I http://dx.doi.org/10.20517/cdr.2018.11

Early observations postulated that sub-population of cells within tumor introduce heterogeneity that impact
the drug response. Such heterogenic phenotypes are closely related to stem cells that express specific markers,
and, as compared to non-CSC cells, exhibit reduced sensitivity to antitumor agents, refractory to therapy
and renders reversible drug tolerant state [3,22] . In line, chemotherapy exert selective pressure that not only
enrich for CSCs but also induce drug tolerant stem cells which further repopulate the treated tumor and
lead to recurrence and aggressiveness. Mounting evidence support that heterogeneity-associated phenotypic
plasticity facilitate acquired resistance development [3,23] .

Recent studies have significantly increased our understanding of the tumorigenic CSCs and molecular
mechanisms that foster their growth and maintenance with protection against chemotherapeutics. Stem-like
cancer cells accumulate mutations and gain survival advantage during therapy through several mechanisms
including their high self-renewal potential, metabolically slow/quiescence non-cycling state, enhanced
expression of drug transporters, anti-apoptotic proteins, and proficient or augmented DNA damage repair
process . Breast cancer stem cells, with signature putative markers such as CD44-high, CD24-low, ESA+
[21]
and ALDH1-high, are negatively associated with disease free survival and apparently, resistance to several
anticancer agents [20,24,25] .

Co-orchestration of EMT-CSC signaling is key in acquired chemoresistance in breast cancer
Regardless of the distinctive mechanisms through which EMT and CSCs phenotype arise, it is convincing that
they share common regulatory mechanisms and their cross-talk is key to initiate metastasis, chemoresistance,
and tumor recurrence [Figure 1] [13,14] . Important evidence provided by Mani et al. , demonstrating the
[26]
ability of EMT to induce cells with stemness laid the basis for establishing the EMT-CSC shared relationship.
Since then several studies have uncovered various mechanisms and pathways involved in these two mutual
processes and how they provide survival advantage to reinforce the evasion from therapy and cause
resistance in breast cancer [19,21,25] . While EMT signaling renders acquisition and maintenance of stem cell
characteristics, CSCs cells use EMT process for metastasis and to evade chemotherapy response . Recent
[14]
reports have reviewed the mechanisms underpinning EMT and CSC in chemoresistance and highlighted
several examples of laboratory and clinical studies indicating the ineffectiveness of radiation, conventional
chemotherapy and advanced targeted therapies towards EMT and CSCs [13,21] .

EMT and CSC shares common signaling pathways to orchestrate the cellular function in terms of tumor
maintenance, metastasis and therapy resistance . Four primary signaling pathways that mediate acquired
[14]
breast cancer resistance through concerted EMT-CSC activation [Figure 1] are described below.

TGF-β-SMAD-dependent and SMAD-independent signaling pathways
Transforming growth factor-beta (TGF-β) is a key regulator controlling cell growth, differentiation and
anti-apoptosis and induce mesenchymal-derived cells to set forth EMT process, migration and invasion
and chemoresistance [27,28] . Sequentially, TGF-β signaling further upregulate CSC-inducing factors including
Nanog, SOX and support CSC maintenance either directly or through microenvironmental changes [26,28] .
Activation of TGF-β trigger SMAD-family proteins and their interaction with EMT-TFs to repress E-cadherin,
an initial step in the EMT process . In turn, activation of SMAD leads to elevation of SOX4/SOX2 expression
[14]
that enable quiescence and cell cycle arrest in CSCs to protect cells from cytotoxicity. However, another
study found TGF-β mediated elevated SOX4 is indeed important for EMT and mesenchymal phenotype .
[29]
TGF-β also involves SMAD-independent signaling to induce EMT and cancer resistance through distinct
tyrosine kinase receptor pathways such as PI3K/Akt and mTOR [27,28,30] . TGF-β induced invasion during EMT
process is orchestrated along with activation of anti-apoptotic signaling including PI3K/Akt and NF-κB
pathways thus apoptosis is prevented during this process . Though Akt transduction and associated nuclear
[27]
localization of FOXO3 are known to be involved in origin of hematopoietic stem cells , function of SMAD-
[28]