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.
Highlights
On a global scale, breast cancer is the most frequently diagnosed cancer, accounting for 29% of total cancer cases, and the leading cause of cancer deaths amongst females[1]
We have shown that silencing SOX2 along with administration of Pax can render the breast cancer stem cells (brCSCs) population less aggressive, with regard to chemo-resistance and migration, via modulation of ABCG2 and TWIST1 expression
Cancer recurrence has been attributed to the impetuous proliferation of cancer stem cells (CSCs) which are not eliminated by conventional chemotherapy, primarily because of elevated expression of drug efflux pumps[21]
Summary
Breast cancer is the most frequently diagnosed cancer, accounting for 29% of total cancer cases, and the leading cause of cancer deaths amongst females[1]. Tumor relapse may be implicated to the meager population of cancer stem cells (CSCs), which contribute to relatively low survival rates in these patients[9]. CSCs share many properties of normal stem cells (NSCs) including a long lifespan, relative quiescence, and resistance to drugs through the expression of drug efflux pumps, an active DNA-repair capacity and resilience to apoptosis. Such a population of drug-resistant pluripotent cells can survive chemotherapy and re-populate the tumor[12]. Selective inhibition and/or eradication of breast cancer stem cells (brCSCs) during systemic chemotherapy would provide TNBC patients a more complete therapeutic option. We have shown that silencing SOX2 along with administration of Pax can render the brCSC population less aggressive, with regard to chemo-resistance and migration, via modulation of ABCG2 and TWIST1 expression
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