title: Epidermal growth factor/heat shock protein 27 pathway regulates vasculogenic mimicry activity of breast cancer stem/progenitor cells.
abstract: Tumor vascularization, which is mainly contributed by angiogenesis and vascularization, is necessary for tumor maintenance and progression. Vasculogenic mimicry (VM), vascular-like channels which are lack of the involvement of endothelial cells, has been observed in aggressive cancers and also involves in tumor vascularization. Breast cancer stem/progenitor cells (BCSCs) have been identified as a subpopulation of breast cancer cells with markers of CD24(-)CD44(+), high aldehyde dehydrogenase activity (ALDH(+)) or could be enriched by mammosphere cultivation. These cells have been proven to be associated with tumor vascularization. Here we investigated the molecular mechanisms in VM activity of BCSCs. By periodic acid-Schiff or hematoxylin-eosin stain, we found that there were VM structures in two xenografted human breast cancer tissues established from CD24(-)CD44(+) or ALDH(+) cells. Only ALDH(+) or mammosphere-forming BCSCs could form tube structures on matrigel-coated surface as similar as microvascular endothelial cells. Inhibition of the phosphorylation of epidermal growth factor receptor (EGFR) by gefitinib or knockdown of EGFR by lentiviral shRNA abolished the in vitro VM activity of BCSCs. By quercetin treatment, a plant flavonoid compound which is known to suppress heat shock proteins, or siRNA-mediated gene silencing, both Hsp27 expression and VM capability of BCSCs were suppressed. Forced expression of phosphor-mimic form of Hsp27 in ALDH(+) BCSCs could overcome the inhibitory effect of gefitinib. In conclusion, our data demonstrate that VM activity of BCSCs is mediated by EGF/Hsp27 signaling and targeting this pathway may benefit to breast cancer therapy.
authors.affiliation: Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung, Taiwan; Department of Microbiology, School of Medicine, China Medical University, Taichung, Taiwan. Electronic address: chlee@mail.cmu.edu.tw.
authors.forename: Che-Hsin
authors.initials: CH
authors.lastname: Lee
authors.affiliation: School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan. Electronic address: e-spider80@hotmail.com.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Wu
authors.affiliation: School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan. Electronic address: enikids@hotmail.com.
authors.forename: Hung-Chun
authors.initials: HC
authors.lastname: Hsieh
authors.affiliation: School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan. Electronic address: yu801001@hotmail.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Center of Stem Cells and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou, Taoyuan County, Taiwan; Department of Pediatrics, University of California in San Diego, San Diego, USA. Electronic address: a1yu@ucsd.edu.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Yu
authors.affiliation: School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: changww@csmu.edu.tw.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Chang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D055551:HSP27 Heat-Shock Proteins; D004815:Epidermal Growth Factor
keywords: Breast cancer; Cancer stem/progenitor cells; Epidermal growth factor; Heat shock protein 27; Vasculogenic mimicry