title: Oxidative stress induces the acquisition of cancer stem-like phenotype in breast cancer detectable by using a Sox2 regulatory region-2 (SRR2) reporter.
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.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Keshav
authors.initials: K
authors.lastname: Gopal
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Abdulraheem
authors.initials: A
authors.lastname: Alshareef
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Hind
authors.initials: H
authors.lastname: Alqahtani
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Bigras
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jamie
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Donna
authors.initials: D
authors.lastname: Douglas
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Norman
authors.initials: N
authors.lastname: Kneteman
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.|Department of Chemical and Materials Engineering, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.|Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.|Department of Chemical and Materials Engineering, University of Alberta, Edmonton, Alberta, Canada.|Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
mesh_terms: D000071916:AC133 Antigen / Q000096:biosynthesis; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D009077:Mucins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D014183:Transplantation, Heterologous
chemical_list: D000071916:AC133 Antigen; C116884:LGR5 protein, human; C460499:MUC15 protein, human; D009077:Mucins; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D006861:Hydrogen Peroxide
keywords: H2O2; Sox2; acquisition of stemness; breast cancer; plasticity