Modulation of SOX2 expression delineates an end-point for paclitaxel-effectiveness in breast cancer stem cells

Abstract

Tumor relapse in triple negative breast cancer patients has been implicated to chemoresistant cancer stem cells (CSCs), which under favorable conditions culminate in tumor re-formation and metastasis. Hence, eradication of CSCs during systemic chemotherapy is imperative. CSCs were sorted using immuno-phenotyping and aldefluor assay. Gene expression profiling of normal breast stem cells and breast CSCs from chemo-treated patients were carried out. Silencing SOX2 was achieved by siRNA method. Mammosphere culture and wound healing assays were carried out to assess efficacy of CSCs. Microarray analysis revealed elevated expression of SOX2, ABCG2 and TWIST1, unraveling an intertwined pluripotency-chemoresistance-EMT axis. Although paclitaxel treatment led to temporary arrest of cell migration, invasiveness resumed after drug removal. The ‘twist in the tale’ was a consistently elevated expression of TWIST1, substantiating that TWIST1 can also promote stemness and chemoresistance in tumors; hence, its eradication was imperative. Silencing SOX2 increased chemo-sensitivity and diminished sphere formation, and led to TWIST1 down regulation. This study eventually established that SOX2 silencing of CSCs along with paclitaxel treatment reduced SOX2-ABCG2-TWIST1 expression, disrupted sphere forming capacity and also reduced invasiveness by retaining epithelial-like properties of the cells, thereby suggesting a more comprehensive therapy for TNBC patients in future.

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2

“…SOX2 is a master regulator that maintains stemness in embryonic stem cells (44) as well as self-renewal of CSCs in several malignancies (36,45). In addition, SOX2 also plays a critical role in drug resistance to paclitaxel (45) and gemcitabine (46) in several cancers. However, the function and epigenetic regulatory mechanism of SOX2 in BCSCs remain to be determined.…”

Salivary gland stem cells: A review of development, regeneration and cancer

“…Elevated SOX2 expression is also associated with increased resistance to chemotherapy agents, although whether this is a direct effect is uncertain (Schrock et al, 2014). However, silencing SOX2 in breast cancer cells in culture leads to increased sensitivity to the chemotherapeutic agent paclitaxel and reduction in mammosphere formation (Mukherjee, Gupta, Chattopadhyay, & Chatterji, 2017), suggesting a direct effect of SOX2 expression on chemoresistance in cancer cells. In addition, elevated or ectopic SOX2 expression has also been associated with the progression of other cancers, including skin SCC (Boumahdi et al, 2014), glioblastoma (Annovazzi, Mellai, Caldera, Valente, & Schiffer, 2011), laryngeal squamous cell carcinoma (LSCC) (Yang, Hui, Wang, Yang, & Jiang, 2014), bladder cancer (Zhu et al, 2017), and small-cell lung cancer (Hussenet et al, 2010).…”

Downregulation of miR‑200c‑3p contributes to the resistance of breast cancer cells to paclitaxel by targeting SOX2

“…In addition, it was found that knockdown of SOX2 in pancreatic ductal adenocarcinoma cells increased the response to small-molecule inhibitors targeting MEK and AKT signaling (18). A recent study indicated that down regulation of SOX2 reduced invasiveness and increased sensitivity to paclitaxel by preserving the epithelial-like properties of breast cancer stem cells (19).…”