Oxidative stress induces the acquisition of cancer stem-like phenotype in breast cancer detectable by using a Sox2 regulatory region-2 (SRR2) reporter
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Keshav Gopal1,*, Nidhi Gupta1,*, Haifeng Zhang1, Abdulraheem Alshareef1, Hind Alqahtani1, Gilbert Bigras1, Jamie Lewis2, Donna Douglas2, Norman Kneteman2, Afsaneh Lavasanifar3,4 and Raymond Lai1,3,4,5
1 Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
2 Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
3 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
4 Department of Chemical and Materials Engineering, University of Alberta, Edmonton, Alberta, Canada
5 Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
* These two authors share the first authorship
Raymond Lai, email:
Keywords: breast cancer, Sox2, H2O2, acquisition of stemness, plasticity
Received: June 08, 2015 Accepted: November 14, 2015 Published: December 16, 2015
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.
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