bioRxiv | 2021
Significance of Oct-4 transcription factor as a pivotal therapeutic target for CD44+/24- mammary tumour initiating cells; aiming at the root of the recurrence
Abstract
Breast cancer (BC) remains one of the deadliest and most frequently diagnosed metastatic cancers worldwide. Cancer stem cells (CSCs) are the cell population within the tumour niche, having an epithelial to mesenchymal (EMT) transition phenotype, high self-renewal, and vigorous metastatic capacity, drug resistance, and ultimate cause of tumour relapse in patients. Identification of targets for apoptosis induction is essential to provide novel therapeutic approaches in breast cancer. Our earlier studies showed that Vitamin C induces apoptotic cell death by losing redox balance in TNBC CSCs. In this current study, we have made an attempt to identify previously unrecognized CSC survival factor/factors that can be used as druggable targets for bCSCs apoptosis regulators isolated from the triple negative breast cancer cell line: MDA MB 468. A thorough literature review was carried out to identify candidates, and Oct-4 was identified as the most promising marker for its unique abundance in cancer and not in normal cells and the contribution of Oct4 to the sustenance of cancer cells. We then validated a very high expression of Oct-4 in the MDA MB 468 bCSCs population using flowcytometry. Loss of function of Oct-4 was carried out using siRNA mediated knockdown in the bCSCs followed by assessing for cellular apoptosis. Our results indicated that Oct-4 knockdown, induced cell death in bCSCs as evident by a change in cellular morphology and positive staining for Annexin-V expression thereby indicating the role of Oct4 in bCSC survival. Moreover, our findings also suggest that Oct-4 directly interacts with Vitamin C as revealed by in silico docking and Oct-4 downregulation inhibited mammosphere formation in vitro. This data, hence, contributes towards novel information about Oct-4 highlighting this molecule as a novel survival factor in bCSCs.