title: Differentiation of breast cancer stem cells by knockdown of CD44: promising differentiation therapy.
abstract: BACKGROUND
  Breast cancer stem cells (BCSCs) are the source of breast tumors. Compared with other cancer cells, cancer stem cells show high resistance to both chemotherapy and radiotherapy. Targeting of BCSCs is thus a potentially promising and effective strategy for breast cancer treatment. Differentiation therapy represents one type of cancer stem-cell-targeting therapy, aimed at attacking the stemness of cancer stem cells, thus reducing their chemo- and radioresistance. In a previous study, we showed that down-regulation of CD44 sensitized BCSCs to the anti-tumor agent doxorubicin. This study aimed to determine if CD44 knockdown caused BCSCs to differentiate into breast cancer non-stem cells (non-BCSCs).
  
  
  METHODS
  We isolated a breast cancer cell population (CD44+CD24- cells) from primary cultures of malignant breast tumors. These cells were sorted into four sub-populations based on their expression of CD44 and CD24 surface markers. CD44 knockdown in the BCSC population was achieved using small hairpin RNA lentivirus particles. The differentiated status of CD44 knock-down BCSCs was evaluated on the basis of changes in CD44+CD24- phenotype, tumorigenesis in NOD/SCID mice, and gene expression in relation to renewal status, metastasis, and cell cycle in comparison with BCSCs and non-BCSCs.
  
  
  RESULTS
  Knockdown of CD44 caused BCSCs to differentiate into non-BCSCs with lower tumorigenic potential, and altered the cell cycle and expression profiles of some stem cell-related genes, making them more similar to those seen in non-BCSCs.
  
  
  CONCLUSIONS
  Knockdown of CD44 is an effective strategy for attacking the stemness of BCSCs, resulting in a loss of stemness and an increase in susceptibility to chemotherapy or radiation. The results of this study highlight a potential new strategy for breast cancer treatment through the targeting of BCSCs.
authors.affiliation: Laboratory of Stem Cell Research and Application, University of Science, Vietnam National University, 227 Nguyen Van Cu, District 5, HCM City, Vietnam. pvphuc@hcmuns.edu.vn
authors.forename: Phuc V
authors.initials: PV
authors.lastname: Pham
authors.forename: Nhan L C
authors.initials: NL
authors.lastname: Phan
authors.forename: Nhung T
authors.initials: NT
authors.lastname: Nguyen
authors.forename: Nhung H
authors.initials: NH
authors.lastname: Truong
authors.forename: Thuy T
authors.initials: TT
authors.lastname: Duong
authors.forename: Dong V
authors.initials: DV
authors.lastname: Le
authors.forename: Kiet D
authors.initials: KD
authors.lastname: Truong
authors.forename: Ngoc K
authors.initials: NK
authors.lastname: Phan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D051927:CD24 Antigen / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D051927:CD24 Antigen; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering