title: Radiation-induced reprogramming of breast cancer cells.
abstract: Breast cancers are thought to be organized hierarchically with a small number of breast cancer stem cells (BCSCs) able to regrow a tumor while their progeny lack this ability. Recently, several groups reported enrichment for BCSCs when breast cancers were subjected to classic anticancer treatment. However, the underlying mechanisms leading to this enrichment are incompletely understood. Using non-BCSCs sorted from patient samples, we found that ionizing radiation reprogrammed differentiated breast cancer cells into induced BCSCs (iBCSCs). iBCSCs showed increased mammosphere formation, increased tumorigenicity, and expressed the same stemness-related genes as BCSCs from nonirradiated samples. Reprogramming occurred in a polyploid subpopulation of cells, coincided with re-expression of the transcription factors Oct4, sex determining region Y-box 2, Nanog, and Klf4, and could be partially prevented by Notch inhibition. We conclude that radiation may induce a BCSC phenotype in differentiated breast cancer cells and that this mechanism contributes to increased BCSC numbers seen after classic anticancer treatment.
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1714, USA.
authors.forename: Chann
authors.initials: C
authors.lastname: Lagadec
authors.forename: Erina
authors.initials: E
authors.lastname: Vlashi
authors.forename: Lorenza
authors.initials: L
authors.lastname: Della Donna
authors.forename: Carmen
authors.initials: C
authors.lastname: Dekmezian
authors.forename: Frank
authors.initials: F
authors.lastname: Pajonk
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D054337:Cell Dedifferentiation / Q000528:radiation effects*; D002454:Cell Differentiation / Q000528:radiation effects; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011123:Polyploidy; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis*; D014965:X-Rays
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors