Cancer stem-like cells (CSCs) are a small population of tumor cells that are capable of self-renewal, producing heterogeneous lineages of cancer cells that comprise the tumor. CSCs are a unique biological subpopulation of cancer cells that could survive indeterminately [
91]. Those cells are characterized by the expression of gene sets associated with embryonic stem cells, the activation of multidrug resistance (MDR) and/or DNA-damage response (DDR) systems [
92,
93].
Although detailed processes of the formation of cancer stem-like cells are still under debate, it is certain that cancer cells must go through the process of cell reprogramming. This process resets differentiated cells to a pluripotent state and can be achieved by nuclear transfer, cell fusion and/or overexpression of certain transcription factors:
Oct-4, Sox2, Klf4, c-Myc (OSKM) [
94] (human homologs:
POU5F1, SOX2, KLF4, MYC). As CSCs overexpress
SOX2, POU5F1, and
NANOG, it is suspected that reprogramming of cancer cells is mediated via overexpression of those transcription factors [
95]. From stemness markers,
SOX2 is best known for its association with anti-estrogen resistance. In vitro studies showed that in ER− endocrine resistant MCF-7 cells SOX2 expression is significantly higher than in ER+-resistant MCF-7 cells [
95]. Other in vitro studies revealed that in ER+ endocrine resistant cell lines, SOX2 expression level is negatively correlated with ER and PR expression level. Interestingly, the high expression of SOX2 was also correlated with increasing histopathological grade during tamoxifen resistance acquisition [
96]. There is growing evidence that
SOX2 expression is highly correlated with resistance mechanisms and epithelial-mesenchymal transition (EMT)-specific gene expression in cancers.
SOX2 is the regulator of: GLI1, FOXA1, mTOR, EGFR, and WNT and/or NF-κB pathway genes expression [
95‐
100]. Those pathways are associated with growth, proliferation, dedifferentiation and resistance in cancer cells. Moreover, overexpression of other stemness markers can lead to hyperactivation of migration, survival and proliferation associated pathways: HEDGEHOG, WNT, NF-κB, TGF-β, NOTCH, ERK/MAPK (reviewed: [
64,
101‐
103]). Activation of these pathways can lead to the acquisition of anti-estrogen resistance, increased invasiveness, migration and formation of distant metastases.