Page 114 - Read Online

Page 298 Ponnusamy et al. Cancer Drug Resist 2019;2:297-312 I http://dx.doi.org/10.20517/cdr.2018.11

INTRODUCTION
Breast cancer is the leading cause of cancer-related death in women globally. Various treatment approaches
such as local therapy (radiation) and systemic therapy including hormones, chemotherapeutic agents and
targeted therapeutic approaches are commonly used in breast cancer patients . Chemotherapy, either as a
[1]
single or combination therapy, is the primary choice of treatment for advanced stage breast cancer patients.
But, non-responsiveness or resistance development to chemotherapy is very common and often result in
treatment failure, hence remains as the major hurdle for the effective clinical management and disease-
free survival of breast cancer patients . Chemoresistance is a dynamic and complex process that can be
[2]
of inherent or acquired during the therapy. Highly heterogenic origin of breast cancer with high degree of
variability in differentiation impacts the chemotherapy sensitivity and resistance development . Besides
[3]
presenting as cross-resistance to combination therapy, prolonged exposure of breast cancer patients to a
single drug may also result in tolerance against multiple structurally and mechanistically diverse, unexposed
drugs that is commonly referred as multidrug resistance .
[2]
Several complex regulatory signaling mechanisms dynamically cross-talk to initiate, establish and maintain
tolerance/resistance to different chemotherapeutic agents in breast cancer. At large, both pharmacokinetics
and pharmacodynamic mechanisms and their reinforcement have been implicated in acquired
chemoresistance . Pharmacokinetic mechanisms such as aberrant expression of drug transporters
[4,5]
(reduced drug influx or increased efflux), drug compartmentalization in intracellular organelles and altered
drug metabolism (inactivation and detoxification) would contribute to tolerance development. Similarly,
pharmacodynamic mechanisms mainly including altered targets expression (both qualitative/quantitative;
over/under expression) and function, genomic instability, mutation of target enzymes, failure to undergo
apoptosis, impaired DNA repair, oxidative stress, microenvironment and cellular reprogramming leading
to phenotypic plasticity including epithelial to mesenchymal transition (EMT) and acquisition of cancer
stem cells (CSCs) characters may eventually contribute to tolerance to cytotoxicity and acquired resistance
development [2,4,5] .

In the recent years, among all the potential mechanisms which contribute to acquired chemoresistance,
increased attention is focused on role of cellular reprogramming with acquisition of EMT and CSC
phenotype [Figure 1] . In addition, mounting evidence on the role of nuclear interaction of reprogramming
[6-8]
factors such as transcription factors (TFs) of EMT and stemness with regulatory protein complexes within
epigenetic landscape further establish the role of epigenetic changes in cellular reprogramming contributing
to acquired chemoresistance [7,9,10] . Moreover, epigenetic modulations are also gaining interest as promising
interventional approaches targeting the cancer cell reprogramming machinery to overcome acquired
chemoresistance in breast cancer [8,11] . In this review, we are mainly discussing previous reports and our recent
findings on epigenetic modifications associated with the regulation of cellular reprogramming processes
such as acquisition of EMT and CSCs phenotype during the acquisition of drug resistance.

CELLULAR REPROGRAMMING
Epithelial to mesenchymal transition
EMT is a conserved, highly complex cellular process that is tightly regulated by various signaling pathways
and transcription factors and controlled by epigenetic reprogramming . During EMT process, epithelial
[9]
cells lose their epithelial features such as cell-cell adhesion and polarity while acquiring the characteristics
of mesenchymal cells, such as increased motility, aggressiveness and invasion. These morphological changes
are accompanied with changes of loss and gain of functional proteins associated with epithelial and
mesenchymal properties respectively. EMT- inducers are group of transcription factors that comprises of the
Snail (Snail/Slug), ZEB (ZEB1/2), and basic helix-loop-helix (TWIST1/2, TCF3) proteins that have specific
target genes involved primarily in EMT process and in recruiting epigenetic regulatory units to exerts their