title: Hypoxia promotes the phenotypic change of aldehyde dehydrogenase activity of breast cancer stem cells.
abstract: Stable breast cancer cell (BCC) lines are valuable tools for the identification of breast cancer stem cell (BCSC) phenotypes that develop in response to several stimuli as well as for studying the basic mechanisms associated with the initiation and maintenance of BCSCs. However, the characteristics of individual, BCC-derived BCSCs varies and these cells show distinct phenotypes depending on the different BCSC markers used for their isolation. Aldehyde dehydrogenase (ALDH) activity is just such a recognized biomarker of BCSCs with a CD44+/CD24-phenotype. We isolated BCSCs with high ALDH activity (CD44+/CD24-/Aldefluorpos) from a primary culture of human breast cancer tissue and observed that the cells had stem cell properties compared to BCSCs with no ALDH activity (CD44+/CD24-/Aldefluorneg). Moreover, we found AldefluorposBCSCs had a greater hypoxic response and subsequent induction of HIF-1α expression compared to the AldefluornegBCSCs. We also found that knocking down HIF-1α, but not HIF-2α, in AldefluorposBCSCs led to a significant reduction of the stem cell properties through a decrease in the mRNA levels of genes associated with the epithelial-mesenchymal transition. Indeed, HIF-1α overexpression in AldefluornegBCSCs led to Slug and Snail mRNA increase and the associated repression of E-cadherin and increase in Vimentin. Of note, prolonged hypoxic stimulation promoted the phenotypic changes of AldefluornegBCSCs including ALDH activity, tumorigenesis and metastasis, suggesting that hypoxia in the tumor environment may influence BCSC fate and breast cancer clinical outcomes.
authors.affiliation: Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shiraishi
authors.affiliation: Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Department of Breast-Thyroid-Endocrine Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Tachi
authors.affiliation: Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Nesrine
authors.initials: N
authors.lastname: Essid
authors.affiliation: Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Ikki
authors.initials: I
authors.lastname: Tsuboi
authors.affiliation: Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Nagano
authors.affiliation: Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Breast-Thyroid-Endocrine Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Bando
authors.affiliation: Department of Breast-Thyroid-Endocrine Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Hara
authors.affiliation: Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohneda
mesh_terms: D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D000071250:Snail Family Transcription Factors / Q000235:genetics; D018874:Spheroids, Cellular / Q000473:pathology; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000444:Aldehyde Dehydrogenase; D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014746:Vimentin; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C000604407:SNAI1 protein, human
keywords: Aldehyde dehydrogenase; breast cancer; cancer stem cells; epithelial-mesenchymal transition; hypoxia-inducible factor-1α