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Page 306 Ponnusamy et al. Cancer Drug Resist 2019;2:297-312 I http://dx.doi.org/10.20517/cdr.2018.11

N-Cadherin expression . Lysine-specific demethylase-1 (LSD1) caused global reduction in H3K9Me2
[73]
and increase in H3K4Me3 and H3K36Me3 during TGF-β-mediated EMT and associated migration and
chemoresistance . Other mechanisms of LSD1 as to EMT process have been reported while they are
[62]
inconclusive for breast tumors . Moreover, EMT associated miRNAs and their modulation through
[8]
epigenetic regulation have been reviewed . These evidences further underwrite the epigenetic landscape
[8]
regulating EMT phenotype to cause acquired resistance.
Epigenetic dysregulation triggering formation of CSC phenotype, maintaining their self-renewal and
apoptotic resistance to chemotherapy have been accruing. Inactivating mutations of epigenetic regulatory
genes including DNMT3A, TET, and PRC2 complex genes aberrantly activate CSC pathways and associated
resistance. Similarly, non-mutational epigenetic aberrations of genes KDM5B, G9a/EHMT2, EZH2, PRC1,
BMI, BRD4, PRMT5, KDM1A/2A, MLL and SWI/SNF involved in dysregulation of CSC-self-renewal,
stemness maintenance and drug sensitivity have been reviewed . Gene silencing mediated through
[6]
DNMTs, EZH2/BMI1 and HDAC1, and activation through MLL and CBP potentially induce aberrations
associated with BCRP, E-cadherin, p16 and Wnt signaling in CSCs . Epigenetic alterations evident to
[52]
induce intratumoral heterogeneity through modulating microenvironment and associated signaling which
supports CSCs including Wnt, TGF-β, and Notch signaling [6,23] . Transient drug-tolerant states generated by
reversible poised chromatin state are regulated through histone demethylase RBP2/KDM5A/Jarid1A and
Notch signaling, thus, help CSCs to evade cytotoxicity mainly by equipping them with complex resistance
mechanisms .
[22]
Similar to epigenetic regulating proteins, the TFs associated with EMT and CSC work coordinately to
activate the downstream effects related to drug resistance. Cancer cells with stemness known to express
high levels of metastatic markers such as Snail1, Twist 1 and FOXC2. Elevated FOXC2 in basal-like breast
cancer cells activate EMT-CSC signaling and reduce drug sensitivity . Similarly, overexpression of Twist
[74]
selects cells with CD44-high/ CD24-low subpopulation that have increased MRP1 expression and activate
β-catenin/Akt pathways to maintain stemness . Similarly, Stem cell factor BMI-1, which is also part of
[75]
PRC1 complex reportedly involve in chemoresistance . Twist 1 directly activates the BMI1 expression and
[76]
they together orchestrate the EMT and stemness induction and maintenance. BMI-1 also shown to regulate
stem cell renewal and induce EMT through its co-ordination with Nanog and NF-κB pathway . Meanwhile
[77]
loss of BMI-1 increased sensitivity of breast cancer cells to doxorubicin .
[77]
Epigenetic deregulation associated with signaling pathways involved in EMT-CSC co-ordination further
implicate their roles in chemoresistance. For example, Wnt ligands and sequester proteins including Wnt5A,
WIF-1, FZD and SFRP known to be modulated through promoter methylation and histone modifications in
breast cancer . Aberrations in epigenetic regulations evaluating TGF-β, Hh and Notch signaling in CSCs
[39]
are scarce. Hh signaling ligands SHH, PTCH1 and SOX17 frequently methylated in breast cancer initiating
cells and Hh effector proteins KIF7 and SUF7 deregulated through histone modifications and miRNA
while GLI1 expression is elevated due to loss of KMT-SETD7 methylase in breast cancer cells thus drive the
aberrant Hh as well as associated NF-κB signaling . Epigenetic mechanisms regulating Notch signaling
[39]
occur through HES, a Notch effector and transcriptional repressor, which recruit histone acetylases/
deacetylases and through hypermethylation mediated silencing of DLL1 (Notch ligand). Taken together,
all these evidences implicate the epigenetic aberrations dictating the activation of EMT-CSC pathways in
acquired chemoresistance in breast cancer.

Impact of treatment schedule on resistant development through acquisition of EMT and CSC-like
phenotype and associated temporal epigenetic changes
In support of the reports discussed in previous section, we are highlighting, in this section, the recent findings
from our laboratory demonstrating the influence of treatment schedules on acquired chemoresistance in