Oxidative stress induces the acquisition of cancer stem-like phenotype in breast cancer detectable by using a Sox2 regulatory region-2 (SRR2) reporter

// Keshav Gopal 1,* , Nidhi Gupta 1,* , Haifeng Zhang 1 , Abdulraheem Alshareef 1 , Hind Alqahtani 1 , Gilbert Bigras 1 , Jamie Lewis 2 , Donna Douglas 2 , Norman Kneteman 2 , Afsaneh Lavasanifar 3,4 and Raymond Lai 1,3,4,5 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 Correspondence to: Raymond Lai, email: // Keywords : breast cancer, Sox2, H 2 O 2 , acquisition of stemness, plasticity Received : June 08, 2015 Accepted : November 14, 2015 Published : December 16, 2015 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 H 2 O 2 tolerance, since siRNA knockdown of Sox2 in RR cells leveled this difference. Interestingly, H 2 O 2 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 H 2 O 2 . 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 H 2 O 2 -induced RU/RR conversion was detectable in a SCID mouse xenograft model and primary tumor cells. To conclude, the H 2 O 2 -induced RU/RR conversion has provided a novel model to study the acquisition of cancer stemness and plasticity.