title: Breast cancer stem-like cells show dominant homologous recombination due to a larger S-G2 fraction.
abstract: The concept of cancer stem cells is generally accepted in different malignancies. We have previously shown that the MDA-MB231 breast cancer cells were more radiation resistant when sorted for the two stem cell markers CD24 and ESA. In this study, we examined a possible mechanism that might underlie this phenotype by looking at cell cycle profile and the effect this has on DNA repair pathways. The cell cycle profile showed that there were more CD24(-) ESA(+) sorted MDA-MB231 cells in the S- and G(2)-phases compared with the unsorted cells, 60 and 38% respectively. Cyclin D and E protein levels supported the cell cycle profile and highlighted the possible involvement of homologous recombination (HR) repair in the radioresistant phenotype. To further support this, CD24(-) ESA(+) sorted MDA-MB231 cells demonstrated statistically significant more RAD51 and less γ-H2AX foci 2 h post 4Gy ionising radiation, compared with the unsorted population. Inhibition of the HR pathway effectively sterilised the CD24(- ) ESA(+) sorted MDA-MB231 cells but had no effect on the unsorted cells or MDA468 control breast cancer cell line. Although the changes we saw were specific to MDA-MB231, these results merit further investigation and can be crucial in identifying a mechanism responsible for cancer stem cells treatment resistance in primary tumors.
authors.affiliation: Gray Institute for Radiation Oncology and Biology, University of Oxford, Churchill Hospital, UK.
authors.forename: Osama
authors.initials: O
authors.lastname: Al-Assar
authors.forename: Tine
authors.initials: T
authors.lastname: Mantoni
authors.forename: Serena
authors.initials: S
authors.lastname: Lunardi
authors.forename: Guy
authors.initials: G
authors.lastname: Kingham
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Brunner
mesh_terms: D001572:Benzofurans / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000473:pathology*; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics*
chemical_list: D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051135:Rad51 Recombinase; C512352:abexinostat