A Twist in the Tale: TWIST1-SOX2 Axis Governs ABCG2-Mediated Paclitaxel Resistance of Breast Cancer Stem Cells

Abstract

Epithelial-mesenchymal transition (EMT) is an important process during development by which epithelial cellsb acquire mesenchymal, fibroblast-like properties and show reduced intercellular adhesion and increased motility.The identification of epithelial-mesenchymal plasticity of breast cancer stem cells provided another level of complexity regarding development of strategies to eliminate these lethal seeds of breast cancer. In determining the association between Sox2, cell migration and expression of EMT markers, we found a persistently high expression of Twist1 and its apparent lack of EMT-like properties during migratory arrest of MDA-MB-231 cells, even after paclitaxel treatment of Sox2-silenced cells. The role of Sox2-dependent Twist1 in maintaining stemness was more prominent when Sox2 expression was high in brCSCs. It can be presumed now that Twist1 expression in presence or absence of Sox2 defines the precise mechanism underlying the possible role of Twist1 in crossroads of pluripotency and EMT of breast cancer stem cells. cancer stem cells comparison their normal counterpart, SOX2, TWIST1 and ABCG2, which are significantly upregulated in paclitaxel-treated triple negative breast tumors. This cascade topluripotency and stemness properties of breast CSCs, mammosphere migratory propensity. Silencing SOX2 with siRNA leads to the down regulation of ABCG2 and TWIST1, confirming that SOX2 governs the expression of these two major CSC markers. Further, paclitaxel treatment in conjunction to si-SOX2, led to i) increased chemosensitivity of breast CSCs to the drug, regulates epithelial-to-mesenchymal transition (EMT) and induces migratory arrest that sustains even after drug removal, simulating a post-chemo treatment condition in patients, and iii) reduces the sphere forming efficiency of CSCs, thus rendering them more susceptible to the anti-cancer effects of paclitaxel.