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Ponnusamy et al. Cancer Drug Resist 2019;2:297-312 I http://dx.doi.org/10.20517/cdr.2018.11 Page 299

Figure 1. Acquired chemoresistance in breast cancer involves cellular reprogramming. Induction of epithelial to mesenchymal transition
(EMT) and cancer stem cell (CSC) facilitate resistance development and tumor recurrence. These processes employ EMT and CSC-
specific Transcription factors (TFs) and activated through key signaling pathways including TGF-β/SMAD, Wnt-β catenin, Notch,
Hedgehog (Hg) and NF-κB/PI3K. Other mechanisms such as increased drug efflux, apoptosis, DNA repair and other microenvironmental
changes in addition to their direct involvement in resistance development, indirectly co-activated/ involved during cellular reprogramming
(EMT-CSC)-mediated chemoresistance

downstream functions . It is important to note that these EMT-TFs also co-ordinates with CSC-TFs to
[9]
induce stemness.

Besides the embryonic development, wound healing and fibrosis, preferential activation of EMT is well
established in tumor metastasis and during chemotherapy to provide growth advantage that drive the clinical
resistance . The degree of EMT and the level of differentiation through heterogeneity may also impact the
[12]
response of the metastatic tumor cells to chemotherapy. EMT-driven chemoresistance may potentially occur
through the common signaling processes that activate not only the EMT but also other survival pathways
including stemness induction [13,14] .

Cancer stem cells
CSCs are sub-population of cells within tumor that possess tumorigenicity as well as capacity to self-renew
after acquiring the genetic and epigenetic modifications needed for adaptation and clonal growth during the
metastatic process and chemotherapy cycles. There are different theories debating the origin of breast cancer
stem cells. Available experimental evidence posits breast cancer stem cells to be derived from mammary
stem cells, mammary progenitor cells or differentiated mammary cells . Functional mutations accrued
[15]
during the quiescent state of the mammary stem cells or progenitor cells induce oncogenic transformation
and perpetrate malignancy [15,16] . Similarly, differentiated mammary cells, upon environmental exposure
such as chemotherapy, de-differentiate to induce de novo stem cell traits [15,17] . These CSCs are epigenetically
unstable and tumorigenic in immunodominant animal models [18,19] . Induction and maintenance of the
stemness are regulated by several key TFs including Octomer binding transcription factor 4 (OCT4), Nanog
homeobox (Nanog), Krupple-like factor 4 (Klf4) and Sex determining region Y box-2 (SOX2). CSCs express
distinctive cell surface markers such as CD24, CD29, CD34, CD38, CD44, CD61, CD90, CD133, CD166,
EpCAM, Epithelial antigen (ESA) and CXCR4, and selective ATB-binding Cassette (ABC) transporters such
as BCRP, and MRP5; selective expression of these markers differentiate the cancer subtypes [19-21] .