Abstract
We have previously identified a novel intra-tumoral dichotomy in breast cancer based on the differential responsiveness to a Sox2 reporter (SRR2), with cells responsive to SRR2 (RR) being more stem-like than unresponsive cells (RU). Here, we report that RR cells derived from MCF7 and ZR751 displayed a higher tolerance to oxidative stress than their RU counterparts, supporting the concept that the RR phenotype correlates with cancer stemness. Sox2 is directly implicated in this differential H2O2 tolerance, since siRNA knockdown of Sox2 in RR cells leveled this difference. Interestingly, H2O2 converted a proportion of RU cells into RR cells, as evidenced by their expression of luciferase and GFP, markers of SRR2 activity. Compared to RU cells, converted RR cells showed a significant increase in mammosphere formation and tolerance to H2O2. Converted RR cells also adopted the biochemical features of RR cells, as evidenced by their substantial increase in Sox2-SRR2 binding and the expression of 3 signature genes of RR cells (CD133, GPR49 and MUC15). Lastly, the H2O2-induced RU/RR conversion was detectable in a SCID mouse xenograft model and primary tumor cells. To conclude, the H2O2-induced RU/RR conversion has provided a novel model to study the acquisition of cancer stemness and plasticity.
Highlights
Similar to many other types of solid tumors, breast cancer (BC) contains a small subset of cells carrying stem-like features, which are commonly labeled cancer stem cells (CSCs) [1]
As we have previously shown that siRNA knockdown of Sox2 can abrogate the SRR2 reporter activity in responsive to SRR2 (RR) cells derived from MCF7 [28], we asked if siRNA knockdown of Sox2 can result in any significant change to their tolerance to H2O2
We previously reported that the expression of several cancer stemnessrelated genes such as PROM1 (CD133), GPR49 (Lgr5) and MUC15 was significantly higher in RR cells as compared to reporter unresponsive (RU) cells derived from BC cell lines as well as primary tumor samples [29]
Summary
Similar to many other types of solid tumors, breast cancer (BC) contains a small subset of cells carrying stem-like features, which are commonly labeled cancer stem cells (CSCs) [1]. In triple-negative BC, CSCs are enriched in the CD44high/CD24low subpopulation [2]. In these tumors, CSCs have been shown to contribute to metastasis, chemoresistance and a worse clinical outcome [3,4,5]. While a few studies have shown that the CD44high/CD24low is a marker of CSCs in this subtype of BC, other studies did not find the association between this immunophenotype and cancer stemness [6, 7]. Hypoxia, which is a cause of oxidative stress, was found to increase the expression of stem cell-associated genes and tumorigenic potential in non-stem cells [13]. Hypoxia in conjunction with H2O2 has been reported to enhance tumor stemness by increasing the fractions of side cell population, which is highly migratory, invasive, and tumorigenic in a variety of solid tumor cell lines [17]
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